Science

Drug-Induced Changes in the Biologic Distribution of Radiopharmaceuticals
William B. Hladik III, Karl K. Nigg, and Buck A. Rhodes

Many pharmacologic agents modify the expected d i s t r i b u t i o n o f radiopharmaceuticals. The authors have attempted to synthesize the literature to date relating to drug-radiopharmaceutical interaction. Further, these interactions were classified as to their
(1) "desirability" (undesirable vs intentional) and t o the (2) specific " m e c h a n i s m o f action.'" Items in the t a b l e s are individually referenced t o a l l o w the reader easy access to source material.
is certainly Ttheinteractionseffect of drugsnot new. As early as 1950s, the upon the thyroid uptake of 1-131 sodium iodide was recognized) In 1974, Ice and Hetzel proposed the identification and reporting of such interactions as potential clinical functions of the nuclear pharmacist. 2 These nuclear medicine scientists, along with others, have established an interdisciplinary approach for screening radiopharmaceuticalpharmaceutical interactions at the University of Oklahoma. 3 Several other medical centers have developed information sources for rapid reference to drugs reported to cause abnormal localization of radiopharmaceuticals. 4'5 At the 1978 Annual Meeting of the Society of Nuclear Medicine, two papers were presented which discussed some theoretical and practical considerations of drug effects on procedures involving radiopharmaceuticals. 6'7 Subsequently, excellent literature reviews of drug-induced alterations in the biodistribution of radiotracers were provided by Lentle et al. 8 and Hodges. 9 However, even since the preparation of these recent publications, much previously unreviewed and/or new data has become available. Therefore, this paper is an updated compilation of the reported modifications in radiopharmaceutical
HE concept of radiopharmaceutical-drug
Depending on interpretation of the underlying mechanism, a few of the interactions which are listed in Tables 1-5 m a y have been logically classified into more than one category. However, each interaction has been listed in the one category which was considered to be most appropriate. As more data becomes available on specific mechanisms, certain interactions may require reclassification.
From the College of Pharmacy University of New Mexico Albuquerque, N.M. Address reprints requests to William B. Hladik, M.S., College of Pharmacy, University of New Mexico, Albuquerque, N.M. 87131. 9 1982 by Grune & Stratton, Inc. 0001-2998/82/1204-0010505.00/0
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biodistribution which result from concomitant drug administration. Several methods exist for logically categorizing the effects of pharmacologic agents on radiopharmaceuticals. These include classification by (1) organ system, (2) individual (nonradioactive) drug or pharmacologic class, (3) type of nuclear medicine study, (4) radiopharmaceutical, (5) desirability of the drug-radiopharmaceutical interaction, and (6) mechanism of the interaction. In an effort to make information on each interaction most easily retrievable, four of the six classifications listed above will be incorporated into this article. The text will be organized according to the particular radiopharmaceutical involved in the interaction. For those radiopharmaceuticals which are used in more than one diagnostic procedure, the specific nuclear medicine study involved in the interaction will also be mentioned. Tables 1-5 will further classify the interactions in terms of the underlying cause or mechanism, as well as the "desirability" of the interaction. These two forms of classification warrant further discussion for a clearer understanding of their meaning. In virtually all instances of drugradiopharmaceutical interaction, the biodistribution of the radiotracer is affected in some manner. In one case, the altered distribution may be simply unanticipated or annoying, or it may actually interfere with the interpretation of the study results, e.g. the effect of Diamox on the biodistribution of tracers used for cisternography. In another situation, the altered distribution may be a result of an intended, or purposeful pharmacologic intervention, ~~ e.g., the diuretic-augmented renogram. This concept of pharmacologic intervention is addressed in the April and July, 1981 issues of Seminars. In a third set of circumstances, the nuclear medicine study may be used to monitor the progress of a course of drug therapy. More specifically, the altered
Seminars in Nuclear Medicine, Vol. XlI, No. 2 (April), 1982
DRUG INDUCED CHANGES IN BIODISTRIBUTION
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Table 1. Examples of RadiopharmaceuticaI-Drug Interactions Mediated Via a Proposed

Radiopharmaceutical Involved in Interaction 1. 2. 3. 4. 5. 6. 7. 8. 99mTcO 499mTcO4 99mTcO.99mTcO4 99mTcO4 99mTc-phosphates 99mTc-phosphates 99mTc-phosphates Nuclear Medicine Procedure Involved in Interaction Meckel's diverticulum Meckal's diverticulum Mackel's diverticulum Brain Brain Bone Bone Bone Drug Involved in Interaction Pantagastrin Glucagon Cirnetidine Corticosteroids Atropine Sodium diatrizoate Indomethacin Etidronate sodium Dichloromethylene diphosphonate Calcitonin Chemotherapeutic agents (various) Heparin Dextrose Vitamin B12 Thyroid hormones Steroid hormones Chemotherapeutic agents Terbutaline Clofibrate Heparin Bronchodilators Vasodilators Cholecystokinin Sincalide Narcotic analgesics Bethanechol Somatostatin Atropine Digitalis glycosides Nitroglycerin Isosorbide Dinitrate Nitroprusside Propranolol Amrinone Dipyridamole Propranolol Minoxidil Digitalis glycosides Furosemide Ethacrynic acid Laxatives Corticosteroids Therapy of pulmonary fibrosis Therapy of sarcoidosis (steroids) Therapy of extrapulmonary tuberculosis Various chemotherapeutic agents Calcitonin Apomorphine ~ L-DOPA Dexamethason Synthetic ACTH
PharmacologicMechanism*
Desirabilityt of Interaction PI PI PI IA or MT PI IA MT MT References 4 4 - 4 6 , 50 4 4 - 4 5 , 47 48-50 54, 56, 59 65 96 100 1 0 4 - 1 0 7 , 110, 111
9. 99mTc-phosphates 10. 99mTc-sulfur colloid
Bone Liver/Spleen
MT IA
108, 109, 1 1 2 118 133-136
11. 9 9 m T c - M A A 12. Xenon 133 Gas/99mTcaerosols 13. Xenon 133 Gas 14. 99mTc-aerosols/99mTc-MAA 15. Xenon 133 16, 99mTc-IDA derivatives 17. 99mTc-IDA derivatives 18. 99mTc-IDA derivatives
Hepatic perfusion Pulmonary V/Q Pulmonary ventilation Pulmonary V/Q Regional myocardial blood flow Hepatobiliary Hepatobiliary Hepatobiliary
MT MT IA PI or MT PI PI IA IA
146 150, 151 158 151 159-161 1 6 2 - 1 6 6 , 170 168 169, 170
19. 20, 21. 22. 23. 24. 25. 26. 27. 28. 29.
99mTc-RBC's 99mTc-RBC's 99mTc-RBC's 99mTc-RBC's 99mTc-RBC's 99mTc-RBC's T1-201 chloride T 1-201 chloride T1-201 chloride T 1-201 chloride T1-201 chloride
MUGA MUGA MUGA MUGA MUGA MUGA Myocardial Myocardial Myocardial Myocardial Myocardial
perfusion perfusion perfusion perfusion perfusion
MT PI or MT MT MT MT MT PI MT or IA MT or IA IA or MT IA or PI PI IA or MT MT MT MT MT MT IA PI
30. Ga-67 citrate 31. Ga-67 citrate 32. Ga-67 citrate 33. Ga-67 citrate 34. Ga-67 citrate 35. Ga-67 citrate 36. Ga-67 citrate 37. Se-75 selenomethionine 38. I- 131 iodomethylnorcholesterol
Tumor/Abscess localization Tumor/Abscess localization Tumor/Abscess localization Tumor/Abscess localization Tumor/Abscess localization Tumor/Abscess localization Tumor/Abscess localization Pancreas Adrenal
186 1 8 8 - 1 9 6 , 203 197 198 199-203 204 197, 2 0 5 - 2 1 1 205, 2 1 2 - 2 1 6 216 205, 2 1 3 - 2 1 7 205, 215, 221 223 234-238 256 148, 241, 261, 263 2 4 1 , 2 6 2 , 263 241,262,264 241,265 266 268 270-272
186
HLADIK, NIGG, AND RHODES
Table 1. (Continued)
Radiopharmaceutical Involved in Interaction 39. I- 131 iodomethylnorcholesterol Nuclear Medicine Procedure Involved in Interaction Adrenal Drug Involved in Interaction Metyrapone Diuretics Oral contraceptives Cholestyramine Propranolol Spironolactone 40. Various agents 41. Various agents 42. Various agents 43. 99mTcO 4 /I-131 Hippuran 44. I- 125 Hippuran 45. 99mTc-DTPA 46. 99mTc-iron ascorbate 47. 99mTc-DTPA 48. In-111 DTPA 0049. In- 111 platelets 50. Xenon- 133 51. Cr-51 RBC's 52. 99mTc-sulfur colloid Gastric emptying Gastric emptying Gastric emptying Renalfunction Renography Urograhy Brain Brain Cisternography Thrombus localization Regional blood flow Spleen Gastroesophageal reflux Metoclopromide Aluminum hydroxide gel Propantheline Furosemide Chlorpromazine Furosemide Corticosteroids Corticosteroids Acetazolamide Heparin Aspirin Benzyl alcohol Adrenaline 8ethanechol Antacids Antacid-Alginic acid Atropine Vasopressin Diuretics Propranolol Ouabain MT IA or MT IA or MT IA PI PI IA or MT IA or MT IA -IA PI MT 273, 274 275 276 279 280 282, 283 285 286 288 290, 291 293 294 295, 296 Desirabilityt of Interaction PI or IA 272 References
53. 99mTc-sulfur colloid 54. 99mTc-sulfur colloid 55. K - 4 0 56. 99mTc-microspheres
Gastroesophageal reflux GI bleed Whole body potassium measurement Regional myocardial blood flow
IA MT MT MT
296 298 299 300
*See the text portion of this paper plus associated references for more detail on each interaction and for the definition of a
pharmacologic interaction.
tSee the text for explanation of "desirability" of interaction. The following abbreviations will be used in this column: IA = interaction is either interfering or annoying MT = the radiopharmaceutical is used to monitor drug therapy PI = the drug is used for a purposeful pharmacologic intervention ~I~--plus other drugs which stimulate the reticuloendothelial system or--plus other drugs which stimulate growth hormone release c~--Although studies have been performed with this agent, no interaction was noted.
distribution of the radiopharmaceutical (from baseline abnormal results) would theoretically reflect the normal response of the body to the pharmacologic action of the administered nonradioactive drug(s), e.g., monitoring the progress of Didronel therapy in Paget's disease. Although an alteration in biodistribution usually signifies a deviation from normality, ~3 in this case it may mark a progression toward normality. Thus, at times, the observed changes in biodistribution patterns of radiopharmaceuticals may be interfering, or "undesirable," whereas at other times, they may be purposeful or "desirable." (See Tables 1-5.) Several authors have suggested ways to subclassify drug-radiopharmaceutical interactions
in mechanistic terms. 2'8 By incorporating the ideas offered by these authors with certain additional information, the following definitions are derived to distinguish the various types of interactions. Multiple examples of each are provided in Tables 1-5: (a) a pharmacologic interaction occurs when either the intended or the secondary physiologic/biologic effect(s) of a drug (those effects that result from a "usual" therapeutic dosage regimen) alters the biodistribution of a radiopharmaceutical. (b) a toxicologic interaction occurs when an overextension of the expected pharmacologic effect or an adverse reaction to a
DRUG INDUCED CHANGES IN BIODIS,FRIBU,rlON

Table 2. Examples of RadiopharmaceuticaI-Drug Interactions Mediated Via a Proposed
187
Toxicologic Mechanism*
Desirabilityl" of Interaction IA IA or MT IA IA or M r IA IA IA M-r IA M,F MT IA IA IA or M-F References 60 61, 62 77 79 81 101 102 122-129 8, 138, 139 141 143 145 147 148
Radiopharmaceutical Involved in Interaction 1. 2. 3. 4. 5. 6. 99mTcO4 99mTcO 4 99mTc-phosphates 99mTc-phosphates 99m,Fc-phosphates 99mTc-phosphates
Nuclear MedicineProcedure Involved in Interaction Brain Brain Bone Bone Bone Bone Bone Avid infarct Liver/Spleen Liver/Spleen Bone marrow Liver/spleen Pulmonary V/Q Pulmonary V/Q
Drug Involved in Interaction Angiographic contrast material Methotrexate Melphalan Corticosteroids Diethylstilbestrol Cytotoxic therapy (unspecifled) Meperidine (intramuscular) Adriamycin Rubidomycin General anesthetics (e,g. halothane) Estrogens Immunosuppressive & chemotherapeutic agents BCNU CCNU Heroin Nitrofurantoin Busulfan Cyclophosphamide:l: Bleomycin Methotrexate Methylsergide Nicotinic acid Methyldopa (I) Ouinidine Adriamycin Rubidomycin Phenytoin Cyclophosphamide $ Bleomycin Busulfan BCG Cytotoxic drugs Immunosuppressive drugs (assoc. with P. carinii pneumonia) Intravenous drugs of abuse (talc) Oily contrast material Ampicillin X Clindamycin Cephalosporins Ampicillin Sulfonamides EZ Ibuprofen Hydrocholorothiazide Cephalexin Sulfinpyrazone Reserpine Methyldopa Phenothiazines ;k Tricyclic antidepresants Metoclopromide Oral contraceptives Diethylstilbestrol Cyclosporin A
7. 99m,rc-phosphates B. 99mTc-phosphates 9. 99mTc-sulfur colloid 10. 99mTc-sulfur col{old 11. 99mTc-sulfur colloid 12. 99mTc-sulfur colloid 13. 99mTc-MAA/Xenon 133 14. 99mTc-MAA/Xenon 133
15. 99mTc-IDA derivatives 16. 99mTc-RBC's 17. 99mTc-RBC's 18. Ga-67 citrate 19. Ga-67 citrate
Hepatobiliary Vascular pool MUGA Tumor/Abscess localization Tumor/Abscess localization
IA IA MT IA IA or MT
173 178 122, 180, 181 233 240-243
20. Ga-67 citrate 21. Ga-67 citrate
Tumor/Abscess localization ,rumor/Abscess localization
IA or MT IA or M,F
8, 244 245,246
22. Ga-67 citrate 23. Ga-67 citrate 24. Ga-67 citrate
Tumor/Abscess localization ,rumor/Abscess localization ,rumor/Abscess localization
IA IA IA or MT
241 247 249,250
25. Ga-67 citrate
,rumor/Abscess localization
IA or MT
251,252
26. Ga-67 citrate
,rumor/Abscess localization
IA
241,253-255
27. 99mTc-DTPA/I-131 Hippuran
Renal Function
IA
277
188
Radiopharmaceutical Involved in Interaction 28. 29. 30. 31. 1-131 Hippuran 99mTc-DTPA 99mTc-microaggregated 99mTc-gluceptate Nuclear Medicine Procedure Involved in Interaction ERPF Renal Function Liver/Spleen Brain Drug Involved in Interaction Iodinated contrast agents Phenacetin Thorotrast Adriamycin Vincristine Actinornycin D Cyclophosphamide *See the text portion of this paper plus associated references for more detail on each interaction and for the definition of a toxicologic interaction. tSee the text for explanation of "'desirability" of interaction. The following abbreviations will be used in this column: IA = interaction is either interfering or annoying MT = the radiopharmaceutical is used to monitor drug therapy PI = the drug is used for a purposeful pharmacologic intervention :l:--plus ~--plus X--plus 9--plus X--plus other drugs that induce other drugs that induce other drugs that induce other drugs that induce other drugs that induce pulmonary interstitial fibrosis RBC antibody formation pseudomembranous colitis interstitial nephritis hyperprolactinemia and gynecomastia Desirabildyt of Interaction IA IA or MT IA or MT IA or MT 278 281 284 287 References
drug (i.e. drug-induced disease) alters the biodistribution of a radiopharmaceutical. (c) a pharmacokinetic interaction occurs when the absorption, distribution, metabolism, or excretion of a drug (indepenRadiopharmaceutical Involved in Interaction 1. 99mTcO4 2. 99mTcO 43. 99mTc-phosphates 4. 99mTc-phosphates 5. Ga-67 citrate 6. Ga-67 citrate 7. Ga-67 citrate 8. ~9. 10. 11. Ga-67 Ga-67 Ga-67 Ga-67 citrate citrate citrate citrate Nuclear Medicine Procedure Involved in Interaction
dent of its pharmacologic effect) alters the biodistribution of a radiopharmaceutical. (d) a pharmaceutical interaction occurs when a physical property of a drug interacts
Drug Involved in Interaction Perchlorate Perchlorate Iron Phospho-soda Iron dextran Iron sorbitol citrate Desferoxamine BAL Desirabilityt of Interaction IA PI IA IA PI PI PI
Table 3. Examples of RadiopharmaceuticaI-Drug Interactions Mediated Via a Proposed Pharmacokinetic Mechanism*

References 44, 51, 52 63, 64 87, 88 91 224, 2 2 5 - 2 2 7 226,228, 229232 232 8, 2 3 1 , 2 3 9 257 258, 259 260 289 297
Meckel's diverticulum
Brain Bone Bone Tumor/abscess localization Tumor/abscess localization Tumor/abscess localization Tumor/abscess Tumor/abscess Tumor/abscess Tumor/abscess localization localization localization localization
Gallium nitrate IA Phenobarbital -Methotrexate IA Mechlorethamine and IA (possibly) vincristine 12. In 113m Placental Iron IA 13. 99mTc-sulfur colloid Hepatic perfusion 5-fluorodeoxyuridine MT 14. (Although no drug-radiopharmaceutical interactions from Table 6 (thyroid studies) are included in Tables 1-5, many of them could be classified as pharmacokinetic due to competitive inhibition of radioactive iodine uptake by the drugs.)
pharmacokinetic interaction.
tSee the text for explanation of "desirability" of interaction. The following abbreviations will be used in this column: IA = interaction is either interfering or annoying MT = the radiopharmaceutical is used to monitor drug therapy PI = the drug is used for a purposeful pharmacologic intervention Note: Since virtually all interactions in each of the mechanistic categories (Tables 1-5) involve alteration of the radiopharmaceutical kinetics, the classification of "pharmacokinetic interaction" refers to an effect caused by a kinetic property of the drug which subsequently alters the kinetics of the radiopharmaceutical, e.g., drug displacement of a radiopharmaceutical from a plasma protein binding site. ~--Although studies have been performed with this agent, no interaction was noted.
189
Table 4. Examples of RadiopharmaceuticaI-Drug Interactions Mediated Via a Proposed Pharmaceutical Mechanism*

Radiopharmaceutical Involved in Interaction 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 99mTcO 499mTcO499mTcO4- (99mTc-RBC's) 99mTc-phosphates 99rnTc-phosphates 99mTc-phosphates 99mTc-sulfur colloid 99mTc-sulfur colloid 99mTc-sulfur colloid 99mTc-MAA 99mTc-RBC's (99mTcO4-) 99mTc-RBC's (99mTc04-) Nuclear Medicine Procedure Involved in Interaction Brain Brain Vascular pool Bone Bone Bone Liver/Spleen Liver/Spleen Liver/Spleen Pulmonary perfusion Vascular pool Vascular pool Vascular pool Myocardial perfusion Drug Involved in Interaction Stannous ion Sulfonamides Stannous ion Iron dextran Aluminum ion Dialysate Aluminum hydroxide Magnesium sulfate Povidone-iodine Magnesium sulfate Heparin Methyldopa Hydralazine Dextrose Sodium bicarbonate Desirabilityt of Interaction IA IA PI IA IA IA IA IA IA IA IA IA IA PI References 66-69 75 70-74 8 4 - 8 6 , 89, 90 93-95 102 132 92 144 92 174, 176, 177 177 182 218
13. 99mTc-RBC's (99mTc04-) 14. T 1 - 2 0 1 chloride
pharmaceuticalinteraction.
tSee the text for explanation of "desirability" of interaction. The following abbreviations will be used in this column: IA = interaction is either interfering or annoying MT = the radiopharmaceutical is used to monitor drug therapy PI = the drug is used for a purposeful pharmacologic intervention
Table 6. Examples of RadiopharmacauticaI-Drug Interactions Mediated Via an Unidentified Mechanism*

Radiopharrnaceutical Involved in Interaction 1. 99mTc042. 99mTc-phosphates Nuclear Medicine Procedure Involved in Interaction Meckel's diverticulum Bone Drug Involved in Interaction Aluminum hydroxide Vincristine Doxorubicin Cyclophosamide Dextrose Methylprednisolone Vitamin D3 Desoxycorticosterone acetate Chemotherapeutic agents, esp. nitrosoureas Phenobarbital Isoprotereool Dexamethasone Desoxycorticosterone acetate Lidocaine Procainamide Insulin with dextrose infusion Adriamycin Cis-platinum See text for listing of drugs Antibiotics (non-specific) Reserpine Desmethylimipramine 6-hydroxy dopamine Desirabilityt of Interaction IA IA 53 76 References
3. 99mTc-phosphates 4. 99mTc-phosphates 5. 99mTc-phosphates 6. 99mTc-sulfur colloid 7. 8. 9. 10. 11. ~12. o~13. 14. 15. 16. 17. 18. 99mTc-IDA derivatives T1-201 chloride T1-201 chloride T1-201 chloride T1-201 chloride T1-201 chloride T1-201 chloride T1-201 chloride Ga-67 citrate Se-75 selenomethionine In-111 leukocytes 1-125 mlBG
Bone Avid infarct Avid infarct Liver/Spleen Hepatobiliary Myocardial perfusion Myocardial perfusion Myocardial perfusion Myocardial perfusion Myocardial perfusion Myocardial perfusion Myocardial perfusion Tumor/Abscess localization Pancreas Abscess localization Myocardial/Adrenal
IA IA PI IA PI IA or PI IA or PI IA or PI IA --IA IA PI or IA IA IA or Pl
92 130 98, 99, 131 142 171, 172 212, 213 215 220 215 213 216 217 8 269 292 301
*See the text portion of this paper plus associated references for more detail on each interaction. tSee the text for explanation of "desirability" of interaction. The following abbreviations will be used in this column: IA = interaction is either interfering or annoying MT = the radiopharmaceutical is used to monitor drug therapy PI = the drug is used for a purposeful pharmacologic intervention co--Although studies have been performed with this agent, no interaction was noted.
190
with a physical property of a radiopharmaceutical, thus altering the biodistribution of the radiopharmaceutical. Although problems caused by improper sequencing of radiopharmaceutical administration could also be included as a type of interaction, these will not be considered here. It is important to realize that each of the definitions above are written in terms of the specific characteristics, or actions, of the therapeutic drug which affect the kinetics (biodistribution) of the radiotracer. Note that if the emphasis of the definition were reversed (i.e., upon the resultant action of the radiopharmaceutical rather than the nonradioactive drug), every interaction could be classified as "kinetic" in nature since in each instance the kinetics of the radiopharmaceutical are altered to some degree. Therefore, when classifying these "interactions," one should not confuse the kinetics of the drug with the kinetics of the radiopharmaceutical.
1-123 AND 1-131 SODIUM IDODIDE AND 99rnTc PERTECHNETATE: THYROID IMAGING, UPTAKE, AND THERAPY
Many of the drug interactions which occur with nuclear thyroid studies have been extensively reviewed by Slingerland in 1955 j and Grayson in 1960J 4 However, for the sake of completeness, this section will serve as a more recent assimilation of the expected interactions. Due to the enormous amount of literature available covering drug-altered biodistribution of thyroid imaging agents 1'1442 the data has been compiled in the form of a chart listing drug name, effect on RAI uptake, suspected mechanism, references and, when available, the expected duration of effect along with special precautions or notes. (See Table 6.) A very useful alternative to radioiodine for thyroid imaging studies is Technetium 99m sodium pertechnetate. ~4'j5 The anion acts as a competitive inhibitor of the iodide transport mechanism; it is not bound in the thyroid and, therefore, not incorporated into the organification process. As a result of the lack of appreciable organification, a thyroid study using Y c O 4- m e a s u r e s only the anion transport function of the gland. All interactions listed in Table 6 which apply to the active transport of iodine would obviously, then, apply also to 99mTcO4-. The effect of drugs on 1-131 NaI therapy has
also been considered. In a review of 186 patients treated with either thioamides and/or 1-131 sodium iodide for Graves disease, Reynolds and Kotchen found that a greater percent of patients who were receiving I-I 31 NaI plus concomitant thioamide therapy required more than one treatment of I-131 when compared to patients receiving only 1-131 NaI therapy. 38 As a result, the bimodal treatment group required a significantly higher average dose of I-131 NaI to achieve cure (13.8 _+ 0.1 mCi vs. 9.6 mCi _+ 0.6 mCi, p < .05). In addition, these authors noted that the incidence of hypothyroidism after I-131 NaI therapy was lower among patients who received concomitant thioamide therapy than among patients receiving 1-131 NaI alone (54% vs. 73%, p < .05), even though the former group received a higher total irradiation dose. When given 2 wk after administration of therapeutic doses of I-131 sodium iodide, carbimazole (60 mg daily) lowered the mean effective half life of radioiodine by more than a day in eleven patients so treated. The drug also variably decreased the radiation dose received from the |-131 therapy by 3%-25% depending on how soon carbimazole was started following 1-131 therapy. 43
99mTc-PERTECHNETATE: MECKEL's DIVERTICULUM IMAGING
One of the many uses of 99mTc-pertechnetate has been for the radionuclidic imaging of Meckel's diverticulum. The radiotracer is localized at the site of ectopic gastric mucosa, possibly by a process of selective uptake in the parietal cells. 44 A number of drugs and hormones including pentagastrin, glucagon, and cimetidine, have been demonstrated to favorably affect the potential for lesion detection in patients with suspected gastrointestinal bleeding caused by Meckel's diverticulum. Premedication with pentagastrin, a parietal cell agonist, increases the uptake of 99mTcO4- in mice stomachs by 65%. 44 The work of Sfakianakis et al. in dogs showed that although pentagastrin does accelerate accumulation of radiotracer in implanted vascularized patches of ectopic gastric mucosa, the net effect of the drug is a lowering of target-to-background ratio due to washout of the intraluminal activity and a concomitant increase in background activity. 4~ A few clinical case reports, however, have provided
DRUG INDUCED CHANGES IN BIODISTRIBUTION Table 6. Drug interactions Involving Radiopharmaeeutieals Used For Thyroid Studies Agent name Action Mechanism The aniOns act as competitive inhibitots of the iodide transport mechanisms. A rebound increased uptake is conceivable following the discontinuance of these anions. References 14-16, 31, 32 Duration of effect Comments
191
Competing Anions Decreased uptake TcO4 , Br , CI04-, BF4-, SCN , SeCN , ReO4 , At-)
Inorganic Iodide Containing Preparations (Kelp, Lugol's Solution, SSKI, vitamin and mineral supplements such as M i Cebrin and Unicap)
Decreased uptake
Large amounts of iodine are contained in these agents. These products are postulated to release iodide, thereby decreasing the specific activity of the radioiodine in the body pool. Lugols' soiution can contain approximately 2.5mg/ drop whereas norreal daily requirement is 1 0 0 - 2 0 0 #g per day.
14-16, 33, 34, 39-42
7 - 3 0 days
Three of the anions have found clinical utility. Perchlorate and thiocyanate are employed in the RAI discharge test for the diagnosis of organification defects. Pertechnetate thyroid studies have become a viable nuclear medicine study. The FDA as well as other governmental agencies has recommended the use of stable iodine as a mechanism for the blockage of thyroidal uptake of free iodine from iodinated radiopharmaceuticals as well as accidental cases of ingestion. The administration of 3 0 100 mg of iodide per day as late as 6 hr after radioiodine intake will result in suppression of more than 90% of normal uptake.
Iodide Antitussives/Ex- Decreased uptake pectorants (EphedOrganidin, Organidin, Pima Syrup, Theo-Organidin, Tussi-Organidin, Tussi-Organidin DM) Topical Iodides (VioDecreased uptake form, Betadine, Iodex, Isodine) Decreased uptake Iodine Tincture
Excess iodine uptake, dilution of body iodide pool
14-18, 41
7 - 3 0 days
Decreased uptake Contrast Media (Conray, Hypaque Meglumine 60%, R e n o - M - 6 0 , Renografin-60, Hypaque Sodium 50% RenoM - 7 6 , Isopaque 280, Renografin76, Renovist, Hypaque-M 75%, Cardiografin, Conray-
Absorption of iodine through the skin abrasion, or lesion Absorption of iodine into the vascular pool Large amounts of iodine are contained in these agents; from 1 2 0 - 4 8 0 mg/ ml. The agents are postulated to release iodide, decreasing the specific activity of the radioiodine in the body pool.
14-17, 19,41
1 m o - 9 mo
14-16, 41
14 days
14, 16, 19, 22, 35, 36
1 wk.-indefinitely
192
Agent name 400, Vascorcy, Isopaque 440, Hypaq u e - M - 9 0 % Angio-Conray Antithyroid Drugs (Propylthiouracil, Tapazole) Decreased uptake Inhibits the metabolic synthesis of thyroid hormones resulting in decreased iodide transport. Caution: following discontinuance of these drugs, a rebound effect may occur. A period of very high uptake may continue for up to 5 days. 14-16, 18, 21, 3 6 - 3 9 , 41 2 - 8 days Steinbach and Donoghue (21 ) performed a prospective study to evaluate the effect of sulfhydryl-containing antithyroid drugs on the outcome of I- 131 therapy of toxic diffuse goiter. The results tend to demonstrate that pretreatment with antithyroid drugs minimized the incidence of hypothyroidism due to radioiodine therapy. T 3 suppression tests are particularly useful in the evaluation of " h o t " nodules. Action Mechanism References Duration of effect Comments
Natural or Synthetic Decreased uptake Thyroid Preparations (Armour, Cytomel, Euthroid, Letter, Proloid, S-P-T, Synthroid, Thyrolar) Salicylates Decreased uptake
Acts by suppressing 14-16, 18, 23, thyroid function 39, 41 (See caution for antithyroid drugs)
1-2 wk
Phenylbutazone
Sedatives, Tranquilizing Agents (Meprobamate, Morphine)
Miscellaneous Agents Na Nitroprusside
Postulated to be due 15, 20, 24 to a suppression of thyroid function. The decreased thyroid function was demonstrated by Austen, (20) et al. to reduce uptake by 4 3 % - 4 5 % of control values. It should be noted that after discontinuance of the medication there was an increase in RAI uptake which lasted 3 - 1 0 days. Decreased uptake Thought to be through 14, 25, 26 a depression of the TSH output, inducing a secondary depression of thyroid activity Decreased RAI in No definitive mecha14, 2 7 - 2 9 euthyroid panism has been estients while not tablished. The studcausing a signifiies of morphine cant alteration in were all conducted patients with in animals. hyperthyroidism Decreased uptake A metabolic by-prod14, 30 uct Of nitroprusside
Up to one wk following cessation of therapy
Unknown
Unknown
193
Agent name Action Mechanism therapy is thiocyanate. This product is thought to inhibit the thyroidal iodide trapping mechanism The reason for the interaction is not fully understood, but there are three suspected effects: (1) Suppression of TSH formation with a resultant decrease of thyroid function (2) Direct effect to inhibit the thyroid (3) Increased renal radioiodine clearance References Duration of effect Comments
Adrenal and Gonadal Steroids; ACTH (Acthar, HP Acthar Gel)
Decreased uptake
14-16, 18
Approximately 8 days
Although most steroids inhibit radioiodine uptake, estrogens have not satisfactorily demonstrated this effect. In fact, animal studies with estrogens shown an i n crease in iodine accumulation by the thyroid. Human studies are inconclusive.
evidence that in the event of normal or equivocal Meckel's diverticulum scans, follow-up imaging using pentagastrin may aid in the identification of the ectopic gastric mucosa. 46 More clinical research is required before any definite conclusions can be made concerning the utility of pentagastrin alone in Meckel's studies. Glucagon prevents peristaltic removal of 99mTc-pertechnetate from the region of the Meckel's lesion, and may also prevent discharge of stomach activity into the small bowel. 45'47As a result of these properties, glucagon alone may enhance lesion detectability in patients with Meckel's diverticulum. However, the combination of pentagastrin and glucagon has been shown to be even more promising than either hormone alone, with excellent lesion visualization and the lowest background activity.4~ Petrokubi et al. have also demonstrated that cimetidine, a potent histamine H 2 receptor blocker, can increase the ability of ectopic gastric mucosa to concentrate radiopertechnetate. 48This effect dramatically improved the visual quality of resultant scans in the two patients reported. Sagar and Piccone concur with this finding and suggest that inhibition of parietal cells, Which probably secrete both acid and pertechnetate, may result in a retention of radioactivity within the normal and, presumably, the ectopic gastric mucosa. 49 Alternatively, cimetidine may exert its
action on the superficial mucosal cells, thus suppressing the secretion of 9 9 m T c O 4 .49 The research of another group disagrees with the concept that pharmacologic intervention should benefit Meckel's diverticulum imaging. Using a gamma camera interfaced with a computer to quantitate gastric radioactivity, Schewesinger and coinvestigators found that pretreatment with either pentagastrin or cimetidine did not significantly affect the total isotope counts in the flagged region of the stomach? ~ These results lend support to the theory that the parietal cells are not involved with 99mTc-pertechnetate uptake in the gastric mucosa, since the effects of both drugs included in this study are mediated via the parietal cells. Perchlorate is known to inhibit gastric uptake of 99mTcO4. Therefore, it is recommended that perchlorate not be given prior to performance of a Meckel's study. 51's~ On the other hand, this agent can be administered at the termination of the procedure to lower the radiation dose to the thyroid. The biodistribution of 99mTcO4- is also altered by an elevation of plasma aluminum levels, resulting in containment of the radiotracer within the vascular space. This phenomenon was examined by Wang et al. in a patient being evaluated for Meckel's diverticulum and who was receiving aluminum hydroxide antacids. 53
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The case report revealed that accumulation of 99mTc-pertechnetate in the stomach and bladder was inhibited until the plasma aluminum level had fallen to nearly normal.
99mTc-PERTECHNETATE: BRAIN IMAGING
Drug interactions that occur with 99mTcpertechnetate, and particularly brain scanning, are among the best known in the nuclear medicine community. The effect of dexamethasone (and other steroids) on brain scans generally reflects improvement in the clinical neurologic status of the patient as a result of therapy. 54 Decreased capillary integrity and increased capillary permeability in cerebral neoplasms and certain other CNS disorders gives rise to local edema;SS 57 99mTcO4- accumulates within this expanded extravascular space. 58'59 By reducing the peritumor edema, steroids suppress the uptake of radiotracer in cerebral tumors. 54 Conflicting data have been presented, however, as to whether steroids affect solely the level of 99mTc-pertechnetate accumulation, or if they additionally alter the boundary of 99mTcOadistribution, i.e., apparent size of the lesion.54.58,59 When cerebral angiography using contrast material was performed prior to 99mTc-pertechnetate brain imaging, an increased localization of radioactivity on the side of angiography was repeatedly visualized by Rosenthal et al. 6~ It is suspected that the contrast agents alter the blood brain barrier. The contrast material seemingly did not interfere with lesion detection, and, in fact, enhanced the concentration of radiopertechnetate in many lesions. In patients with methotrexate-induced leukoencephalopathy, ventricular or meningeal patterns of r a d i o n u c l i d e u p t a k e have been observed. 61 Makler et al. have seen increased radioactivity in the cerebral ventricles on a 99mTcO4- brain scan in a patient with acute lymphocytic leukemia receiving intrathecal methotrexate therapy for CNS involvement.62 This abnormal activity was attributed to ventriculitis associated with methotrexate toxicity. Pharmacologic intervention with perchlorate, atropine, and stannous ion has become common practice in nuclear medicine. The prior or concomitant administration of perchlorate to block
concentration of 99mTcO4 in the thyroid, salivary glands, and choroid plexus, and the injection of atropine to inhibit secretion have virtually always been "intentional" procedures. 63-65 In contrast, the interaction of tin with 99mTcpertechnetate was considered "interfering" even as late a s 1 9 7 7 . 66-68 It was specifically recommended that procedures which involved the use of radiopharmaceuticals containing stannous ion (especially bone imaging agents) should be performed after all other nuclear studies requiring 99mTcO4-, e.g., brain scanning. 68'69This advice is basically still applicable. However, the use of stannous ion to reduce pertechnetate within the red blood cell, resulting in the labeling of 99m technetium to hemoglobin, 7~ eventually became one of the primary thrusts behind the development of several currently used nuclear medicine procedures which necessitate blood pool visualization. 73'74 Prior medication with sulfonamides has been linked to the observation of intense vascular pooling of radioactivity following the injection of 99mTc-pertechnetate for brain imaging. 75 Although none of the three patients involved had recently under gone another nuclear medicine study (i.e., they had not previously been given a Sn +2 - containing compound), a 75% labeling efficiency of red blood cells was documented in one of them. Corresponding studies in sulfonamide-treated rabbits showed a variable, but generally increased, radiolabeling of RBC's by 99mTcO4-. 75
99mTc-PHOSPHATES/PHOSPHONATES: BONE IMAGING
Lutrin et al. noted intense renal parenchymal uptake of radioactivity on 17 bone scans of children who had been treated with vincristine, doxorubicin, and cyclophosphamide, either alone or in combination. 76 This phenomenon was only encountered if at least one of these drugs was administered no more than one week prior to the bone scan. The authors suspect that the effect is due to a direct action of the three antimitotic drugs on the renal tubules, although no reduction in renal function could be determined by measurement of standard clinical laboratory tests (e.g.B.U.N., urine specific gravity, etc.). On a bone scan performed following regional
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chemoperfusion of melphalan and actinomycin D, a diffuse increase in activity in both the bones and soft tissue of the involved limb was observed. 77 A biodistribution pattern of this type is related to erythema and hyperemia secondary to the drug therapy rather than to the primary malignancy. It is well known that long-term steroid therapy induces bone mineral depletion, particularly in postmenopausal women, elderly patients, immobilized patients, diabetic patients, and those on long term therapy. 78 As a result, a patient so treated will commonly demonstrate a generalized decrease in skeletal uptake of bone imaging agents. 79 Certain drugs, including estrogens, digitalis, cimetidine, and spironolactone, among others, promote gynecomastia, s~ Ramsingh et al. have reported a case of bilateral uptake of 99mTcpyrophosphate into the breasts of a 59 year old man who had been receiving diethylstilbestrol for therapy of prostatic carcinoma. 8~ The reason for this breast uptake is unknown, although the authors refer to the work of Zimmer et al. 8z and Schmitt et al. 83which suggests that it may be due to the binding of the bone seeking radiopharmaceuticals to receptor sites on enzymes such as acid or alkaline phosphatase (found in varying quantities in soft tissues). Several authors have seen accumulation of 99mTc-bone imaging radiopharmaceuticals in sites where intramuscular iron dextran had been administered, most commonly the gluteal area.S4 86 Multiple possible mechanisms of localization have been proposed including hyperemia in response to the administered iron injection, local complexing of the 99mTc-bone agent to liberated ions or proteins, combination of reduced technetium with ferric hydroxide as it is released from the iron dextran complex, and formation of a dextran 99mTc-phosphate complex. One problem which constantly plagues nuclear medicine diagnosticians is that of a poor bone to nonbone radiotracer distribution ratio which is often encountered on bone scans. This problem may be a result of either reduced skeletal uptake or an increase in "background" activity. Parker and coworkers postulate that iron overload may actually decrease the uptake of 99mTc-bone imaging agents in the skeleton, and
that excessive iron "may account for some of the poor quality bone scans seen clinically. ''87 They support their hypothesis with four patient cases, one of which was receiving supplemental iron therapy. These same four patients demonstrated a relative increase in renal activity. Research performed by McRae et al. also lends credibility to this idea of iron excess as a cause of altered distribution of bone agents. 88 Their work showed that elevated local concentrations of iron or calcium in vivo might facilitate the dissociation of 99mTc from the phosphate/phosphonate moiety with possibly some form of ligand exchange occurring, the result of which may carry activity to the kidneys. They noted substantial renal activity derived from bone imaging compounds in the presence of ferrous sulfate even when no carrier kidney-agent ligand was present. Further evidence is supplied by a case report in which an intravenous injection of iron dextran resulted in decreased bone uptake and increased radioactivity in the kidneys. 89 Choy et al. observed a reduction in skeletal radioactivity accompanied by marked blood pool labeling in a patient who underwent 99mTc-pyrophosphate scintigraphy 24 hours following an intravenous iron dextran infusion; however, no comment was made about the intensity of renal uptake. 9~ The possibility exists that a bonding occurs between the circulating iron dextran complex and the 99mTc-labeled phosphorus compounds, with a resultant pooling of radioactivity in the blood. 9~ This mechanism of bonding may be similar to that which takes place after intramuscular injection of iron dextran in gluteal muscle, as discussed in the previous paragraph. Another case report of poor tracer uptake in bone led the authors to speculate that this occurrence may have resulted from saturation of bone binding sites by phosphorus ions in the PhosphoSoda medication which the patient was receiving on a daily basis. 91 Although poorly documented, dextrose may also affect the distribution of 99mTc-bone imaging compounds. Sampson has reported that in some children receiving intravenous dextrose, 99mTc-medronate "may go straight to the kidn e y s . ''92
Visualization of the liver on a bone scan may, in certain patients, be due to increased serum aluminum. In one study, rats pretreated with 50
196
mg of AI +3 concentrated 99mTc-etidronate to a high degree in the liver. 93 This observation is substantiated indirectly by the fact that when AI +3 is added to 99mTc-bone agents in vitro, liver uptake is obvious on the resultant s c a n s . 94 Even more convincing is the research of Jaresko et al. who investigated the effect of varying plasma aluminum concentrations on the biodistribution of 99mTc-diphosphonate in rats. 95 Their findings show that no alteration in distribution occurs at less than 10 ug/ml circulating aluminum, but that increased kidney uptake takes place at a plasma aluminum concentration of 20 ug/ml and liver uptake at 40 /~g/ml or greater. Comparable blood levels may be encountered clinically in a limited number of patients receiving antacids, particularly those with gastrointestinal obstruction or impaired renal function. 95 Following the administration of 99mTc-pyrophosphate, marked renal and hepatic uptake was seen on the bone scan of a patient who had subsequently received 100 ml of sodium diatrizoate shortly after the injection of the radiopharmaceutical. 96 The renal activity can be explained by the osmotic effect of the intravenous radiographic contrast material which inhibited the normal tubular resorption of the 99mTc-pyrophosphate. According to Crawford et al. a similar effect might be expected in patients taking osmotic-type diuretics. 96 Several investigators have reported that the likelihood of hepatic uptake of bone imaging agents increases as the pH of the pharmaceutical preparation r i s e s . 93'97 Chaudhuri discovered that kidney uptake is also high at an alkaline p H . 93 It is possible, then, that the pH of the contrast agent promoted an in vivo environment conducive to hepatic (and renal) uptake of the 99mTc-pyrosphosphate. Vitamin D3, in a single intravenous dose of 50,000 USP units administered to rats, caused a significant reduction in the skeletal uptake of 99mTc-pyrophosphate. 98 Although this interaction could be deleterious to bone imaging, it may actually prove to be beneficial to avid infarct imaging, as is discussed in detail in the following
section.99
The role of prostaglandin E in the scintigraphic detection of bone cancer was explored by Otsuka et al. using tumor-bearing rabbits. In certain animals treated with indomethacin, an antiprostaglandin agent, the appearance of a
positive bone scan was significantly delayed when compared to rabbits receiving the anticancer drug mitomycin C. The authors speculate that indomethacin suppresses prostaglandininduced bone resorption in skeletal metastases. Joo A so called "sickle-sign," an area of diffuse activity around the calvarium, was observed on bone scans by Creutzig and Dach in 60 of 108 (56%) breast cancer patients receiving intensive (although unspecified) cytotoxic therapy. 1~ This figure compares to 3.5% of "control" patients on hormonal therapy for prostatic cancer who also demonstrated this phenomenon. The sickle sign induced by cytotoxic therapy can potentially be misinterpreted as bony metastases, although use of a vertex view normally enables the physician to discriminate between iatrogenic and metastatic disease) ~ Localization of 99mTc-MDP in soft tissue has been observed following intramuscular injection of meperidine. Presumably muscle injury caused by the injection resulted in focal uptake of the radiopharmaceutical at the site of the injection.~~ A group of investigators from the Netherlands found that in chronic hemodialysis patients who received bone-seeking radiopharmaceuticals (and were dialyzed prior to imaging), the resultant scintigrams demonstrated gastric radiotracer uptake in 17 of 35 cases, and thyroid uptake in 2 of thirty-five. ~~ However, these results were only seen in dialysis patients who were connected to a "single patient unit" with recirculating dialysate. Thin layer chromatography revealed only 0.6% free pertechnetate in the radiopharmaceutical preparation. All ten patients examined initially with nonrecirculating dialysate and all 24 (of the original 35) patients who underwent repeat scintigrams using nonrecirculating dialysate had no signs of distribution of radioactivity to the stomach. When the nearly-pure 99mTc-diphosphonate was intentionally added to the recirculating dialysate system, radiochemical purity tests showed an increase in free pertechnetate to 31.2% within 5 minutes. The authors conclude that a radiochemical interaction with constituents of the dialysate fluid may result in the formation of 99mTcO4- in the closed dialysis system. Skeletal scintigraphy is routinely used to assess the therapeutic response of Paget's dis-
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ease t~176 and various forms of cancer. ~~176 Of particular interest is the fact that although some of the therapeutic agents used for Paget's disease, e.g. dichloromethylene disphosphonate and etidronate disodium, are very similar or even identical in chemical structure to the compounds used for bone scanning, they do not seem to modify the potential of normal bone for tracer uptake. 1~176 On the other hand, these same agents are effective in decreasing the ratio of radioactive pagetic bone to radioactive symmetrical noninvolved bone as monitored by nuclear imaging?0a.~t~ These therapeutic effects are particularly prominent during the first six months of treatment.~04 Numerous clinicians have observed that radioactivity distribution to metastatic bone lesions is diminished after chemotherapy and/or hormonal therapy, t~2-~8 It is only fair to mention, however, that investigators do not concur on the type of scintigraphic changes to be expected in responding patients. ~~176 This inconsistency may, in part, be due to the fact that metastases from various types of cancers do not accumulate 99mTc-phosphates (or other bone imaging radiotracers) in exactly the same mann e r . 109
We can anticipate that studies will be reported in the future which demonstrate iatrogenic effects via bone blood flow regulation. In Charkes summary of the mechanisms of skeletal tracer uptake, he outlines thirteen specific mechanisms, three of which are directly related to bone blood flow.~2~ Hence, we expect that any drug which alters bone blood flow (or any of these other parameters e.g., metabolic activity of bone) will, in turn, affect the biodistribution of radioactive tracers which localize in bone.
99mTc-PHOSPHATES/PHOSPHONATES: AVID INFARCT IMAGING
Attempts have been made to monitor the cardiotoxicity of both rubidomycin,~22 and particularly adriamycin (doxorubicin), ~23-~26 with 99mTc-pyrophosphate/medronate myocardial scans. Although localization of radiotracer into the myocardium of patients receiving adriamycin has been inconsistent,123 this inconsistency may not necessarily reflect a lack of sensitivity of the procedure for detecting drug toxicity. In fact, due to the various shortcomings of most correlative diagnostic modalities,~26 the true value of
99mTc-pyrophosphate (Tc-PYP) myocardial studies in humans is difficult to fully assess without exposing the patients to undue risk, i.e., by continuing therapy beyond that which is clinically advisable in order to note changes in myocardial uptake of the radiopharmaceutical. For instance, the report of Chacko et al. 126 could be substantiated if there were evidence to show that the eight patients in their series who demonstrated diffuse myocardial uptake of 99mTcpyrophosphate (but with no other evidence of toxicity) would eventually manifest gross symptoms of cardiomyopathy should they be continued on doxorubicin therapy. 127This avenue is obviously n o t viable research methodology. Certain authors, however, believe that adequate techniques are presently available for comparison with Tc-PYP imaging in patients with suspected adriamycin toxicity. ~2v Animal studies with doxorubicin have shown a good correlation between histologic changes and degree of positivity of the scan? 28'~29 Furthermore, since the animal myocardial images returned to normal following discontinuation of the drug in spite of progressive histologic change, the authors theorize that the scan may detect early, possibly biochemical, changes in the heart tissue. Repeat DC countershock regularly produces myocardial necrosis in dogs, which can then be detected by 99mTc-pyrophosphate imaging. Using this experimental model, Schneider et al. looked at the effect of pretreatment with methylprednisolone on subsequent myocardial injury. 13~ The ratio of radioactivity in the damaged myocardial tissue compared to radioactivity in surrounding normal myocardial tissue was greater in dogs who had been given methylprednisolone. It is important to note that this finding resulted from a reduced uptake of Tc-PYP in normal myocardium rather than to an increased accumulation of Tc-PYP in the lesion. The mechanism for this phenomenon was a decrease in circulating Tc-PYP and an acceleration of TcPYP urinary clearance induced by the steroid therapy. Therefore, pretreatment with corticosteroid did not modify the degree of myocardial necrosis, as confirmed by various techniques used in conjunction with Tc-PYP imaging. However, if the data concerning ratio of lesion to nonlesion myocardial uptake of Tc-PYP was considered without the benefit of correlative data, the oppo-
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site conclusion might have been reached. The results of this study clearly illustrate that "the intrinsic effects of an intervention upon radionuclide kinetics must be established prior to using that radionuclide to evaluate the intervention's efficacy.''~3~ Carr and collaborators found that the lesion (target) to bone (nontarget) uptake of 99mTcpyrophosphate in a rat model of myocardial necrosis was favorably influenced by the administration of desoxycorticosterone a c e t a t e (DOCA) and Vitamin D3. 99 In the case of D3, the concomitant hypercalcemia and hyperphosphatemia induced by the vitamin may be partially responsible for the increase in lesion to bone (L/B) ratio. Data supporting this concept showed that when serum calcium and serum phosphate levels were elevated independently of each other via the respective parenteral administration of these ions, a change in the L / B ratio was observed in the same direction as that with vitamin D3 but not to the same magnitude. On the other hand, DOCA had an effect on the L / B ratio equivalent to that of D 3 but without an associated increase in serum calcium concentration. Additionally, the administration of DOCA resulted in a potentially beneficial imzrease in the relative radioactivity measured in the lesion compared to that of blood which, theoretically at least, should also assist in lesion detection. Although the net effect on the L / B ratio was similar for the two steroidal compounds, D3 more regularly decreased uptake of radioactivity in bone whereas DOCA consistently increased the accumulation of tracer in the lesion. These results are consistent with those reported previously.98 Potential adverse effects upon the infarcted myocardium or the skeleton which may occur when these drugs are used clinically in an analogous manner have not gone unnoticed. 99'13~
99mTc SULFUR COLLOID: IMAGING OF THE RES Pulmonary accumulation of 99mTc-sulfur colloid has been associated with many factors, and drugs are no exception. The findings of Bobinet et al. suggest that aluminum ions may be absorbed into the blood from the intestine in high enough concentrations to cause in vivo formation of colloid macroaggregates, which are then capable of lodging in the pulmonary capillaries, m This group has observed sequestration of radio-
colloid in the lungs of a patient receiving 30 ml of Mylanta (aluminum hydroxide) every hour. The patient's serum aluminum level was markedly elevated when this phenomenon was seen. In addition, when a sample of 99mTc-sulfur colloid was mixed with the patient's plasma, a white precipitate developed, However, upon discontinuation of the antacid and a subsequent fall in serum level, a corresponding decrease in pulmonary uptake of colloid was realized and no precipitate was formed in vitro. Heparin, dextrose, vitamin B~2, thyroid hormones, and steroid hormones (including estrogen), are known stimulators of the reticuloendothelial system to varying degrees. ~33 136 Any of these drugs may elevate the number of free intravascular macrophages which, in turn, migrate to the pulmonary microcirculation where they theoretically phagocytize injected radiocolloid. Case reports in the literature to validate this theory are lacking, however. We have seen several cases of 99mTc-sulfur colloid lung uptake in patients receiving heparin, but a cause-effect relationship has not been established. Lentle et al. have provided a possible explanation for the abnormal increase in splenic uptake of 99mTc-sulfur colloid (relative to the liver) seen in patients who have recently undergone surgery. 8 These authors postulate that the reduced hepatic blood flow 137 and hepatotoxicity ~38 associated with general anesthetic agents (e.g. halothane) may alter the hepatic radiocolloid extraction efficiency, resulting in a reversal of the normal liver-spleen colloid distribution pattern. In addition, although there is much controversy over the frequency with which halothane, methoxyflurane, enflurane and other anesthetics may adversely affect the liver, ~38 the changes induced by these drugs may be manifested by a scan appearance characteristic of acute hepatitis and/or hepatic necrosis, in which case the colloid "shift" previously mentioned does not necessarily occur. 139 Both estrogens and androgens can produce neoplastic transformation in the liver. ~4~ Estrogens are not infrequently associated with benign hepatic adenoma and focal nodular hyperplasia. According to Jhingran et al., these two types of lesions can generally be differentiated by their representation on a colloid liver-spleen scan. 141 Mottled uptake of the radiopharmaceutical
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usually characterizes focal nodular hyperplasia, whereas hepatic adenoma presents as focal "cold" areas. At times, however, focal nodular hyperplasia may also present as filling defects. Androgens are more often associated with malignant liver tumors, ~4~ which would also produce focal areas of decreased colloid uptake. In a study of 15 patients with various types of primary cancers, liver-spleen scans were performed just prior to initiation of chemotherapy and at three times during the course of therapy.142 The effect of 13 different chemotherapeutic agents upon sequential images was investigated. Results show that modifications in colloid distribution are "infrequent, minor and transient. ''~4~ However, three distinct patterns of image alterations were attributed to the chemotherapy: heterogeneous radiocolloid distribution, minimal to moderate hepatomegaly, and a shift of the radiopharmaceutical from the liver to the extrahepatic reticuloendothelial system. Nitrosoureas were the agents most frequently associated with scan abnormalities. lmmunosuppressive and chemotherapeutic agents have also been found to affect the results of bone marrow imaging with 99mTc sulfur colloid, presumably secondary to the marrow injury (compromised hematopoiesis reflected by granulocytopenia) which these drugs induce. 143 The specific effect seen on the scans is described as an extended reticuloendothelial marrow pattern, i.e., "visualization of marrow RE activity in the axial skeleton and beyond the proximal one-third of the humerus or femur" (emphasis added). ~43 This pattern was observed in 12 of 15 (80%) patients on chemotherapy. This same abnormal pattern of distribution was not seen in a control group of patients with granulocytopenia caused by factors other than chemotherapy. Three patients receiving chemotherapy did not demonstrate an extention of RE phagocytic activity on the colloid studies. These patients had a relatively mild and/or transient granulocytopenia compared to the other twelve patients. The authors propose that an extended reticuloendothelial marrow pattern should be heeded as a warning of limited marrow tolerance to chemotherapy. A troublesome "clumping" of 99mTc-colloid particles, with subsequent entrapment in the vasculature of the lungs may occur in patients receiving magnesium sulfate. 92 According to
Sampson, this interaction is likely to be observed in infants who "fail to thrive" and are therefore being treated with this drug. 92 An example of pharmaceutical-radiopharmaceutical interaction not associated with drug administration, i.e., an in vitro interaction, was reported by Fisher, et al. 144 Periodically, these authors were noticing evidence of excessive blood pool activity and free pertechnetate on 9 9 m T c sulfur colloid studies. The routine procedure for dispensing of the radiopharmaceutical included swabbing the vial top with a povidone iodine preparation prior to entering the vial to withdraw a unit dose. Upon further investigation, it was discovered that unless the povidone iodine was allowed to dry on the septum, the antiseptic solution would enter the vial with the needle, and partially or completely oxidize the technetium product to 99mTcO4. Diminished splenic uptake of 99mTc-sulfur colloid was seen by Armas et al. on the scintigram of a patient with a diagnosis of macrocytic anemia, pulmonary fibrosis, and thalamic neoplasm treated with radiation as well as combination BCNU and C C N U chemotherapy. ~45 The poor trapping of the colloid probably resulted from a chemotherapy-induced "functional hyposplenia. ''~45
9 9 m T c - M A A , MICROSPHERES, AEROSOLS,
AND XENOX-133 GAS" VENTILATION AND PERFUSION STUDIES OF MULTIPLE ORGANS
99mTc-MAA, long recognized for its value in the assessment of pulmonary perfusion, is now also being utilized to evaluate hepatic perfusion. Kaplan et al. have found that, in a majority of cases, the response of hepatic metastases to chemotherapy could be predicted by monitoring the perfusion of local hepatic defectsJ 46 A decrease in the focal defect size and/or hepatic size normally indicated a favorable response, whereas nonperfusion of the defect or visualization of extrahepatic collections of radioaggregrates were interpreted as meaning no response to drug therapy. These investigators believe that this method "has the potential for directing catheter placement, precisely defining drug flow rates, and predicting responders to intraarterial therapy. ''~46 As mentioned in the section on 99mTc-sulfur colloid, magnesium sulfate therapy apparently causes clumping of colloidal radiopharmaceuti-
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cals. This phenomenon has been reported with 99mTc-MAA as well.92 A study of eighteen narcotic addicts (with no symptoms of pulmonary disease) revealed that 27% (5/18) of the subjects had normal perfusion and ventilation studies, 46% (8/18) had defects in regional perfusion only, and the remaining 27% had abnormal perfusion and ventilation studies. ~47 The perfusion defects seen were primarily diffuse and nonsegmental; the abnormalities in regional ventilation were characterized by delayed clearance of the Xe-133 gas. It is likely that the changes in regional perfusion resulted from occlusion of small pulmonary vessels by foreign bodies in the injected heroin or to subsequent granuloma formation, whereas the cause of the noted defects in ventilation is not known. Crystal et al. have described the use of 99mTc-MAA and Xenon-133 gas for evaluation of idiopathic pulmonary fibrosis. ~48Furthermore, a number of drugs including nitrofurantoin, busulfan, bleomycin, methotrexate, and methylsergide, to name just a few, have been implicated in causing pulmonary fibrosis. 14~ With some slight extrapolation it can be anticipated that perfusion and ventilation nuclear medicine studies may also be of some value in the workup of the drug-induced form of this disease. The effect of terbutaline therapy has been studied using 99mTc-aerosols and Xenon133. jS~ Following subcutaneous administration of the drug to asthmatic patients, both types of ventilation images reverted toward normal. However, when terbutaline was given by inhalation, a greater improvement occured in the 99mTc-pertechnetate aerosol images compared to the xenon gas images, presumably because the drug aerosol and the radioaerosol have a similar pattern of distribution, i.e., the large airways. Case reports and directed scientific investigations have strongly correlated hepatic accumulation of radioxenon with the presence of excess fat in the liver. 152 157 This liver uptake of xenon has occurred most commonly in patients with conditions which predispose to fatty liver, namely diabetes mellitus, obesity, alcoholic fatty infiltration, hypercholesterolemia, and coronary artery disease. According to research performed by Kitani and Winkler, the observed xenon retention may represent elevated liver triglyceride content in these patients. 153With this knowledge,
Shafer and Bianco have speculated that if drugs such as clofibrate exert their effect by interfering with the conversion of triglycerides to fatty acids in the liver, they may indirectly enhance xenon retention.158 At least two examples of adjunctive pharmacologic intervention exist in this category of radiopharmaceuticals. 151'j59'161 When baseline pulmonary perfusion-aerosol nuclear imaging is inconclusive in differentiating between thromboembolic and bronchospastic disease, Taplin and Chopra recommend the performance of repeat studies following pharmacologic intervention before resorting to angiography. TM If both studies revert to normal patterns after 1-2 days of intensive therapy with bronchodilators and heparin, a diagnosis of airway disease can be made and embolism excluded. On the other hand, should the perfusion studies remain unchanged, the probability of pulmonary embolism is high. Although coronary arteriography can define the anatomy of the coronary arterial tree and contrast cine ventriculography can depict the contractility of the left ventricle, these techniques do not evaluate the resultant hemodynamic significance of any lesions detected. The Xenon-133 washout technique may help accomplish this in selected patients by evaluating regional myocardial blood flow.159 Here again, pharmacologic intervention, i.e., vasodilators, may add another dimension to the study, although certain technical factors must be taken into consideration when interpreting results. 160,161 For instance, the timing of the xenon injection with respect to drug administration is critical.
9 9 m T c - I M I N O D I A C E T I C ACID (IDA)
DERIVATIVES: HEPATOBILIARY IMAGING
As a means to reduce the probability of obtaining a false positive diagnosis of cystic duct obstruction with cholescintigraphy, several authors have advocated the use of cholecystokinin (CCK) or sincalide, its synthetic analog, both of which stimulate gallbladder contraction. 162-165 Some clinicians choose to give the CCK prior to the initial injection of the radiopharmaceutical; 162 others prefer to wait and administer the stimulant plus a second dose of 99mTc-HIDA only if the gallbladder is not visualized initially. 163't64If the latter method is utilized, it may be possible to distinguish chronic from acute
201
cholecystitis in many cases, although the extra time involved is a slight disadvantage. By quantitating the contractile response of the gallbladder to CCK using 9 9 m T c - I D A derivatives, certain acalculous gallbladder diseases can also be identified. 166 Morphine and several related narcotic analgesics are known to cause a significant elevation in intrabiliary pressure at normal therapeutic dosage levels. 167 This effect, although observed inconsistently in patients, may begin as quickly as 5 min post injection and persist for 2 hr or more. The rise in pressure is due to biliary tract spasm and a constriction of the sphincter of Oddi; both of these mechanisms may prevent emptying of bile into the duodenum. 167 Since 9 9 m T c - I D A radiopharmaceuticals are eliminated in the bile, their delivery to the small bowel may theoretically be delayed as a result of these narcotic-induced effects. Pope and Bratke have observed a significantly increase liver-to-duodenum transit time of 9 9 m T c - H I D A in 6 acutely ill patients who were admitted through the emergency room where they had been given pain medication. ~68 Using a crossover methodology, Lira et al. studied the effect of a combination of 10 mg morphine and 1 mg neostigmine in 15 individuals who were confirmed to have no organic extrahepatic obstruction. 3~ Visualization of the common bile duct and upper gastrointestinal tract was delayed in nearly all subjects, and a prolonged increase in gallbladder activity was seen in those patients who had not undergone cholescystectomy. Thus, these drugs may induce a pattern of distribution which resembles obstruction of the common bile duct. Further prospective animal and clinical research to study this interaction is currently under consideration. The effect of cholinergic blockade and cholinergic stimulation on gallbladder emptying was determined scintigraphically by Fisher et al. using 99m T c - I D A compounds. 169Their findings showed that atropine decreased the maximal gallbladder response to a standard meal from 77.9 + _3% to 56.6 +_ 9%. Conversely, whereas no _ gallbladder emptying occured over 2 hr in the absence of a meal, bethanechol induced a response of 25.1 _ 6.4% under these same conditions. Both atropine infusion and somatostatin infusion were found by Rock et al. to inhibit gallbladder emptying in response to meals or sham
feeding. 17~ Simultaneous infusion of sincalide obliterated the inhibitory effect of somatostatin. 170 The differentiation of extrahepatic biliary atresia from neonatal hepatitis can be aided by the administration of phenobarbital for at least five days prior to performance of 99mTc-IDA hepatobiliary scintigraphy, t7~'~72 The major advantage to this procedure is avoidance of the need to image beyond 24 hr, which would normally necessitate use of the diagnostically inferior radiotracer, 1-131 rose bengal. Maid et al. discovered that phenobarbital enhances and accelerates the biliary excretion of 99mTc-IDA derivatives. ~TjThus, if phenobarbital is given, the diagnostician can rapidly determine the status of the extrahepatic biliary tract in the jaundiced neonate (i.e., within a 24 hr period). On two separate occasions in the same patient, cholescintigrams failed to demonstrate significant extraction or excretion of 9 9 m T c - H I D A by the liver; elimination of the radiopharmaceutical was predominantly via renal pathways. ~73In each instance, the patient's liver function tests were abnormally elevated. The diminished liver uptake of 9 9 m T c - H I D A was attributed to the hepatotoxicity of nicotinic acid, a drug which the patient had been taking in high doses for approximately six months. Upon the subsequent discontinuation of the nicotinic acid, the patient's blood test results returned to normal values, and a normal radionuclide hepatobiliary study was obtained.
99mTc-RED BLOOD CELLS
(Sn+2-99mTcO4-RBC): IMAGING OF THE VASCULAR POOL
Hegge et al. reported that when a heparinized catheter was used as the injection port for in vivo red blood cell (RBC) labeling, the result was consistently poor quality studies showing diminished cardiac chamber activity and increased renal uptake and excretion. ~74 This pattern of distribution is not totally surprising since 99mTc-heparin, which is used experimentally for myocardial studies, is known to accumulate to a large extent to the kidneys. ~75 The effect of therapeutic doses of heparin upon the biodistribution of Tc-RBC's has not been demonstrated clinically. However, Thrall and Swanson implied that heparin may have contributed to the poor in vivo labeling of RBC's in an isolated case,
202
although the patient was concomitantly receiving 26 other drugs as well; therefore, conclusive evidence to support this hypothesis is not available. 176 Zimmer and colleagues have investigated the effect of heparin and four other widely used drugs on in vivo radiolabeling of red blood cells using an in vitro model. 177Two of these, methyldopa and hydralazine, significantly decreased the labeling efficiency, possibly through oxidation of the stannous ion which may occur when the Sn +2 is added to whole blood containing either drug. Clinically relevant concentrations of lidocaine, quinidine, and heparin did not alter red cell labeling in this system. In certain patients, RBC antibody formation may be the primary factor causing inefficient radiolabeling of RBC's in vivo. Moreover, drug therapy may be partially responsible for this RBC antibody formation. Leitl et al. determined labeling efficiency in 40 consecutive patients, and in eight of them found an RBC radiolabel of less than 50%, compared to a mean value of greater than 90% in the other 32 patients. ~78 Each of these eight patients either had diseases or were receiving medications associated with RBC antibody formation; five were taking methyldopa and/or quinidine, both of which are known to induce a positive direct Coomb's test in some individuals, j79 To discover if this same phenomenon would occur under controlled conditions in vitro, packed red cells were incubated with anti-RhD serum prior to labeling the cells with Tc-99m using the Brookhaven kit method. A decrease of 22% (95% control vs. 73% post incubation) in labeling efficiency resulted. Another procedure that has become routine in many nuclear medicine departments is the monitoring of adriamycin and/or rubidomycin therapy with 9 9 m T c - R B C multigated (MUGA) blood pool studies. Cardiomyopathy is the major factor in limiting the effective use of these drugs, and M U G A scintigraphy has proven to be a relatively sensitive and reliable method for quantitating the degree of cardiac dysfunction resulting from treatment with adriamycin. ~22'18~ We have seen one case locally in which marked renal uptake and lack of blood pool radioactivity was noted in a patient scheduled for a M U G A study. 182 Due to the lack of vascular access, the stanous pyrophosphate and the subsequent 99mTcO4- were administered through a
slowly running (TKO) IV line. It is possible, although not proven, that the 99mTc labeled to the dextrose in the intravenous solution rather than to the RBC's as was expected. The observed pattern of distribution is similar to that reported with compounds such as gluceptate, gluconate, mannitol, and sorbital, all of which are related to dextrose in chemical structure and can be complexed with technetium. 183 185 Radionuclide angiography has also been used to study the effect of several drugs on left ventricular (LV) function. In 14 patients with stable ischemic heart disease, chronic digoxin therapy did not significantly affect ejection fraction at rest or at peak exercise. 186 However, as reflected by end-diastolic and end-systolic volume indexes, the drug did improve LV function at peak exercise in those patients with an ejection fraction greater than 50% at rest. ~86 Although coronary vasodilation with dipyridamole is useful as an adjunct to TI-201 imaging, Sochor et al. found that it was not suitable for gated blood pool wall motion studies. 187 The pharmacologic intervention of nitroglycerin ( N T G ) in radionuclide angiography studies, on the other hand, is now recognized as a valuable means for differentiating viable, albeit ischemic, myocardium from fibrotic cardiac muscle when localized regions of myocardial asynergy have been observed. Improvement in these abnormally contracting segments of left ventricle after the administration of N T G indicates that the asynergy or dyssynergy is reversible and that normalization of the myocardial wall contraction will very likely occur in response to revascularization surgery. ~88 193Additionally, an increase in radionuclide ejection fraction (EF) following sublingual N T G is normally accompanied by a decrease in both end-diastolic and end-systolic volumes with a variable effect on stroke volume depending on whether the patient is or is not experiencing acute ischemia at the time of the study. ~ 94-196 Two other vasodilators have also been investigated. Another nitrate studied with radionuclide ventriculography, isosorbide dinitrate, has been shown to improve exercise LV performance, and thus may increase exercise tolerance in selected patients with ischemic heart disease. ~97The data presented by Shah and coinvestigators suggests that reduction of elevated capillary wedge pressure and/or arterial pressure caused by sodium
203
nitroprusside may decrease ischemia in hypofunctioning regions of the left ventricle in patients with acute myocardial infarction, thereby improving LV performanceJ 98 The resting EF is unaltered and exercise induced changes in EF are minimized in patients with coronary artery disease on propranolol therapy. 199'2~176 Berger et al. concur that high dose oral propranolol prevents exercise induced LV dysfunction, and therefore can potentially interfere with the diagnosis of coronary artery disease in patients undergoing radionuclide angiography. 2~ The results of first-pass radionuclide angiography studies performed on healthy adult volunteers indicate that alterations in heart rate are responsible for the observed effects of proprano101 on left ventricular function both at rest and during exercise. 2~ Both propranolol and N T G were included in an investigation which evaluated theaccuracy of cardiac output determinations using data produced by multiple gated equilibrium scintigraphy and confirmed by the Fick technique. 2~ The drugs were used to produce hemodynamic changes which could subsequently be measured by the two methods. A high degree of concordance was noted between the radionuclide count data and the Fick cardiac output before and after drug administration. The only discordant response between the two methods was recorded after propranolol was given at peak exercise. The effect of the inotropic drug, amrinone, upon left ventricular ejection fraction was determined by gated radionuclide imaging in five patients with advanced congestive heart failure. Ejection fraction increased from a control value of 14 8 percent to 21 _+ 8 percent following administration of amrinone. 2~
THALLIUM-201 CHLORIDE: MYOCARDIAL PERFUSION IMAGING
The drug effect which has received the most notoriety in this radiopharmaceutical class is that of coronary vasodilation caused by dipyridamole.187.205 2~1 In the dog model, dipyridamole produced at 60% increase in Thallium-201 (T1201) myocardial concentration. 2~ Several clinical studies have reported that dipyridamole is as effective as exercise in producing regional myocardial perfusion abnormalities which can then be detected by T1-201 imaging in patients with coronary artery disease (CAD). 2~176 Whereas
most investigators have compared pharmacologic versus physiologic induced coronary vasodilation by observing TI-201 images immediately following intervention, Sklar et al. studied delayed thallium redistribution after employing these same techniques. 2'~ Patterns of TI-201 redistribution were observed at 4 hr and 24 hr following injection of the radioisotope. In patients with single vessel CAD, redistribution was seen at 4 hr in those who had exercised but not in those who had received dipyridamole; at 24 hr redistribution was complete in all patients with single vessel CAD. In contrast, redistribution was evident at 4 hr in every patient with multiple vessel CAD, regardless of whether they had exercised or had received dipyridamole. Using the isolated in situ gracilis muscle as a model, Zaret found that administration of propranolol reduced TI-201 uptake by a factor of 2-2y2 times normal. 2~2 Measurement of T1-201 myocardial uptake in intact, beating mouse hearts resulted in the finding that propranolol decreases myocardial concentration of the radiotracer by approximately 23%. 213 Costin and Zaret reported a 32% lower T1-201 uptake in samples of dog myocardial tissue after IV propranolol as compared to controls. 2j4 The research of Hamilton et al. revealed a smaller, but significant, decrease in the left ventricular T1-201 concentration in dogs given propranolol, although this difference was not apparent in the myocardial-to-background ratios which were derived from external imaging techniques. 2~ Another investigator demonstrated a 25% reduction in propranolol heart/liver fractional uptake ratio, but from the data presented it is difficult to discern if this effect was due to an absolute reduction in T1-201 myocardial uptake or rather to an increase in liver uptake. 2~5When measuring the effect of several variables on the first pass myocardial extraction fraction of T1-201, Weich et al. observed an insignificant change from control values in response to propranolol administration. 216 A wide range of data is also available with regard to the effect of digitalis glycosides on T1-201 uptake by myocardial tissue. Acetyl strophanthin was shown to have virtually no effect upon the first pass myocardial extraction fraction of TI-201. 216 Hamilton et al. also saw no significant change in the T1-201 myocardialto-background ratio in dogs given intravenous
204
digoxin. 2~ On the other hand, Schelbert et al. determined that oubain reduced both the absolute myocardial concentration of T1-201 as well as the rate of radionuclide uptake into mouse myocardium. 2~3 Costin and Zaret noted a 22% reduction in the accumulation of T1-201 in dog heart muscle after injection of digitalis. 214 According to Bossuyt and Jonckheer, the administration of cardiac glycosides to mice resulted in a 10% lowering of heart/liver T1-201 uptake ratio] ~5 Adriamycin, another glycoside (not a digitalis glycoside, however) with cardiac effects, can cause "an acute reversible reduction in myocardial TI-201 uptake that is prevented by pretreatment with digoxin. ''2~7 Several other drugs are known to affect the biodistribution of TI-201. Dilantin was found to decrease T1-201 heart activity by nearly 39% in rats, but it apparently does not affect heartto-blood or heart-to-muscle ratios; consequently this drug may not alter the appearance of T1-201 scans in clinical practice. 3~ Although Hamilton et al. have shown that furosemide has no effect upon T1-201 uptake in dog myocardial contractile tissue, 2~ Bossuyt and Jonckheer report that chronic furosemide therapy without concomitant potassium replacement can increase the concentration of TI-201 by 20% in mouse hearts. 2~5 Depending on the dosage used, intravenous sodium bicarbonate has been noted to increase myocardial TI-201 concentration between 1.36 and 1.8 times that measured in matched control dogs. 2~8Dexamethasone 2~5and isoproterenol 2~2'2j3 have both been found to enhance uptake of TI-201 by the heart. In fact, isoproterenol can reverse the decrease in T1-201 uptake induced by propranolol. 2~2 In dogs treated with minoxidil, the first pass T1-201 myocardial extraction fraction was reduced. 2j6 Likewise, lidocaine lowers the heart-to-liver T1-201 fractional uptake ratio. 2~5Additional studies have determined that neither procainamide 2~3nor insulin with dextrose infusion 2~6cause an alteration in the localization of TI-201 into myocardium. Waschek et al. studied 62 patients receiving any of seven cardioactive drugs in multiple combinations, and concluded that TI-201 images were insignificantly affected by these drugs, as indicated by the myocardium-to-background ratios. 219 Finally, the elimination of thallium can also be altered by drug therapy. Desoxycorticosterone acetate increases the renal clearance of thallium
in adrenalectomized dogs, 22~and the renal excretion of thallium via the kidneys is elevated approximately two-fold in rats receiving high doses of ethacrynic acid or furosemide. 22j-223
Ga-67 CITRATE: TUMOR AND INFLAMMATORY PROCESS IMAGING
Several pharmacologic agents have been used in conjunction with Ga-67 citrate in an effort to improve the target to non-target ratio of the resultant images. When iron dextran was administered to abscess-bearing rabbits 24 hr after the injection of Ga-67, the abscess-to-muscle ratio increased to more than twice that obtained in an untreated group of rabbits. 224However, when the iron was given prior to or simultaneously with the Ga-67, the abscess-to-muscle ratio was actually poorer than that in the control group. Other research confirms these results. 225'226The mechanism for this effect is probably displacement of Ga-67 from plasma protein binding sites by the iron which then causes an increased elimination of the radiopharmaceutical. Extrapolating from this animal data, it would appear that the specific timing of this intervention (post Ga-67 injection) would be of paramount importance in the clinical setting, since accumulation of the Ga-67 into the lesion must be permitted to occur before administration of the iron dextran. Smith and Dendy, however, have had success in lowering soft tissue background in a series of 147 patients by administering iron-sorbitol citrate before G a - 6 7 citrate. 227 According to the authors, this procedure made earlier diagnosis possible. Desferoxamine has also been investigated as a contrast-enhancing agent for abscess and tumor imaging with Ga-67 citrate. 226"228230 The resultant effect in animals is similar to that seen with iron dextran, but is accomplished by formation of a chelate complex of gallium with desferoxamine which is then excreted in the kidneys. Hoffer has not found as much success in clinical trials with this complexing agent because relatively smaller doses than that used in animals studies must be given to avoid toxicity. TM Looking at the situation from a slightly different perspective, Oster et al. examined the utility of several chelating agents for reducing radiation exposure after completion of a Ga-67 citrate study. 232 The whole body radiation dose was lowered by 25% and 11.9% (compared to
205
controls) when desferoxmine was given at 5 hr and 24 hr respectively after intravenous injection of Ga-67 citrate. BAL decreased Ga-67 blood activity by 41.3% while also reducing activity in other organs to a lesser degree. 232 During the routine diagnostic workup of a patient with testicular carcinoma, Lentle and Starrveld noticed a distribution pattern indicative of lymphoma on a Ga-67 citrate scan. 233 Correlative studies, however, revealed that the patient did not have metastatic seminoma and that, in fact, all lymph nodes were apparently normal; thus, the observed Ga-67 uptake in the lymph nodes could not be immediately explained. It was ascertained later that the patient had been receiving the anticonvulsant phenytoin (Dilantin), a drug which is known to initiate various alterations in lymphoid tissue. Subsequently, 20 patients taking therapeutic doses of phenytoin were prospectively studied to determine the effect of the drug on Ga-67 citrate imaging. In five of the 20 subjects a lymphoma-like pattern of distribution was again seen, although only one of these patients definitely had lymphadenopathy. z33
Bowel cleansing is generally recommended as a standard procedure prior to Ga-67 scanning to assure accurate interpretation of abdominal images. 234'235This is accomplished by a variety of cathartics with differing mechanisms and specific sites of action. Recently, however, two independent investigator groups using different laxative combinations provided evidence that these orally administered bowel preparations given daily during the study do not significantly alter the degree of intestinal gallium interference on the resultant scans nor do they shorten the delay in scan interpretation. 236'237 Based on the results of a prospective study of 309 patients undergoing Ga-67 scintigraphy, Novetsky et al. suggested that the lack of cleansing effect seen in many patients is due, at least in part, to poor compliance with the laxative regimens rather than to an intrinsic failure of drug action. 238 A negative effect on tumor and tissue localization results from the administration of carrier gallium. Increased renal excretion of Ga-67 and preferential distribution of the radiotracer to bone occurs in patients who are concomitantly receiving nonradioactive gallium nitrate for cancer chemotherapy. 8'23~'239 Detection of iatrogenic inflammatory lesions
has been reported not infrequently with Ga-67 citrate scintigraphy. Despite normal chest X rays, abnormal lung uptake was seen by MacMahon and Bekerman in six patients with lymphoreticular neoplasia who had received multiple cycles of chemotherapy consisting of cyclophosphamide, vincristine, plus various other chemotherapeutic agents. 24~Since cyclophosphamide is included in the list of drugs which are associated with pulmonary interstitial fibrosis,8'14~ it is likely that this drug is responsible for the altered biodistribution. 241 Diffuse pulmonary localization of Ga-67 citrate has also been visualized in patients with interstitial pulmonary inflammation induced by busulfan 242 and bleomycin,243 in individuals with BCG pneumonitisy 44 as well as in patients with Pneumocystis carinii infection who have been receiving cytotoxic and/or immunosuppressive medications. 245'246 In the latter case, Ga-67 uptake may be disproportionate to chest radiographic changes. Vascular talc granulomatis caused by long-term intravenous drug abuse is another pathologic finding characterized by intense pulmonary uptake of Ga-67 citratefl 4~ Furthermore, the antecedent injection of oily contrast medium used in lymphangiography should be considered among the possible reasons for the appearance of a uniform pattern of radiogallium distribution in the lungs. 247 Accumulation of Ga-67 in the colon, kidneys, and mammary tissue has, at one time or another, been attributed to drug-induced disease. Pseudomembranous colitis may occur post-therapy with nearly any antibiotic, but most commonly is related to treatment with ampicillin, clindamycin, and the cephalosporins. 248One manifestation of this disease is the concentration of Ga-67 citrate in the inflamed intestinal mucosa and pseudomembranes, which should not be confused with the presence of luminal fecal activity. 249'25~ No evidence of documented mild to moderate nephrotoxicity could be demonstrated by Ga-67 citrate imaging in rats who had received prolonged regimens of aminoglycosides or amphoterecin B. 25~ In humans, however, avid uptake of Ga-67 by the kidneys occurred in at least 9 cases of interstitial nephritis associated with the administration of ampicillin, sulfonamides, ibuprofen, hydrochlorothiazide, cephalexin, or sulfinpyrazone.252 Although breast uptake of Ga-67 is often described as a normal variant seen in postpartum
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or pregnant women, it is also related to druginduced gynecomastia and hyperprolactinemia.253 255 This phenomenon has happened most frequently in women taking such drugs as reserpine, various phenothiazines, metoclopromide, as well as oral contraceptives, 241'253'254but has also been noted in two male patients on diethylstilbestrol t h e r a p y for prostatic-associated dise a s e s . 253,254
Steroids are reported to suppress radiogallium localization in CNS tumors, 256 presumably by a mechanism similar to that previously described for 99mTc-pertechnetate brain imaging. The sensitivity of Ga-67 for the detection of brain neoplasms was decreased from 95% in a nonsteroid group to 64% in patients treated with steroids. 256 To test their hypothesis that binding of Ga-67 to hepatic microsomal enzymes may account for some of its liver uptake, Hubbard and his colleagues injected phenobarbital into mice for six consecutive days. 257 Such therapy is known to stimulate an increase in the amount of microsomal enzymes and smooth endoplasmic reticulum. The mice were injected with Ga-67 citrate on day eight and then sacrificed on day nine. Biodistribution studies revealed no significant difference in the amount of Ga-67 in treated vs. untreated livers when data was corrected for liver weight. Thus, the subcellular binding site for gallium is probably not any of the cellular components which are affected by barbiturate therapy.257 Thymic uptake of Ga-67 citrate has been reported by Donahue et al. to occur at a higher frequency in pediatric patients with various neoplastic diseases than in children with inflammatory diseases. 3~ The authors postulate that this uptake may be due either to tumor invasion or to "increased activity of thymic medullary epithelial cells and regeneration of thymic lymphocytes during recovery from involution induced by certain chemotherapeutic agents. ''3~ In addition to those already mentioned, three additional chemotherapeutic agents have been observed to alter the biodistribution of radiogallium. Methotrexate simulates the effect of carrier gallium (which was discussed previously), 258'259although probably via a different mechanism. Since methotrexate elevates serum iron levels by temporarily inhibiting incorporation of iron into erythrocytes, Chilton et al. propose that
an increased number of gallium binding sites in the serum are occupied by iron following administration of methotrexate. 259 This obviously results in more unbound Ga-67 which subsequently promotes both its elimination and its localization in bone. Mechlorethamine and vincristine sulfate (and also irradiation) decreased the whole body retention of Ga-67 citrate in rats, accompanied by an increase in bone deposition and increased urinary excretion. 26~ Based on equilibrium dialysis data, it was theorized that these effects were mediated somewhat by an alteration in Ga-67 serum binding, at least in the case of whole body irradiation and mechlorethamine, a radiomimetic agent. Several unusual distribution patterns have been seen with cisplatinum. Lentle et al. related their experience with four patients taking this drug. 8 Each of them had greatly reduced liver activity and high blood levels of Ga-67. One patient had gastric uptake and two had renal localization of the radiotracer with no clinical or laboratory evidence of abnormalities in these organs. Even though cis-platinum was highly suspect as the cause for these effects, it is admittedly difficult to single out one drug in patients who are on multiple chemotherapeutic agents, as was the situation with these latter four patients. 8 Gallium 67 citrate scanning is valuable not only in the diagnosis and staging of disease, but is also useful for evaluation of the responses to drug therapy in these same disorders. Specifically, some of the conditions in which Ga-67 is helpful for monitoring drug therapy include: idiopathic pulmonary fibrosis, sarcoidosis, extra-pulmonary tuberculosis, various tumors of the head and neck, carcinoma of the lung, and Paget's dise a s e . 148241'261-266 In the case of sarcoidosis, it is unclear as to whether Ga-67 citrate imaging is simply more sensitive than other modalities in detecting response to steroid therapy, or whether the "steroids interfere with the gallium uptake mechanism independent of their effect on the disease. ''z62 In addition, recent administration of cytotoxic drugs can actually result in false negative Ga-67 scans in patients with lung carcinoma.24~.26v Hoffer, in his teaching editorial, remarks "Proposed mechanisms of Ga-67 localization in tumor are highly speculative and controversial with much contradictory evidence. ''231 In spite of the controversy, however, it seems that both iron
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and iron-binding proteins may be involved in the process; hence, drugs which alter ferrokinetics, or which influence the synthesis, behavior, or regional concentrations of iron-binding proteins should be suspect as possibly affecting Ga-67 studies. Furthermore, it seems that leukocytes may, at times, compete with other tissues for Ga-67 or they may be responsible for movement of Ga-67 within the body; therefore, drugs with immunoregulatory activities might also be suspect of Ga-67 "iatrogenesis."
Se-75 SELENOMETHIONINE: PANCREATIC IMAGING
hormone production in females with known androgen excess. 27~ Synthetic ACTH (Cortrosyn) can be given to enhance images when the adrenals are poorly visualized initially.27~ Other drugs which alter adrenal cortical function and adrenal scintigraphic imaging are listed in tabular form along with associated mechanisms and references in a review article by Gross et al. 272 Among these, metyrapone, diuretics, oral contraceptives, and cholestyramine affect scan appearance by increasing tracer uptake, whereas propranolol and spironolactone decrease the accumulation of tracer in the adrenals.
MISCELLANEOUS RADIOPHARMACEUTICALS
Two studies using different animal models have monitored the effect of a total of 18 drugs upon Se-75 selenomethionine uptake by the pancreas. 26~'269 Out of all the drugs studied, only propylthiouracil increased the pancreas-to-liver concentration ratio in rats (5.00 + 0.10 s.e.m. compared to 4.00 + 0.04 s.e.m, in controls) following 3 days of therapy with the drug at a dose of 50 mg/kg. 269 A significant decrease in the pancreas-to-liver Se-75 selenomethionine ratio was obtained with the drugs L-DOPA, apomorphine, insulin, theophylline, carbachol, stilbestrol, alloxan, hydrocortisone, and cyclohexamide, whereas perchlorate, carbimazole, thyroxine, and triiodothyronine had no effect on the observed ratio. Atkins and Sore suspect that the effect of L-DOPA and apomorphine in mice is mediated via a stimulation of growth hormone release by the pituitary. 268
I- 131 IODOMETHYL 19-NORCHOLESTEROL (NP-59): ADRENAL IMAGING
The following information pertains to those radiopharmaceuticals with a lower incidence of interaction with drugs (to date). A one or two sentence summary will briefly describe each interaction:
Pharmacologic intervention with dexamethasone suppresses uptake of radiotracer in the normal gland; therefore, an early finding of non-suppressed radioactivity in the adrenals following administration of dexamethasone is strongly suggestive of an aldosteronoma, particularly if the uptake pattern is obviously unilateral. 27~Hoefnagels et al. found that NP-59 imaging, performed after longterm treatment with dexamethasone, had a sensitivity of 89% in the detection of aldosterone-producing adenomas. 271 In addition, since androgens do not suppress ACTH, this same technique using dexamethasone can also be employed when the need arises to differentiate between ovarian and adrenal
(1) Various isotopes and test meals." Gastric Emptying Studies Metoclopromide shortened the gastric emptying time of patients with diabetic gastroenteropathy to normal values in 8 of 12 patients studied. 273 This drug had been previously investigated. 274 Hurwitz et al. found that aluminum hydroxide gel (antacid) and propantheline both significantly delay gastric emptying. 275'276 However, the research of Deering et al. suggests that antacids directly and indirectly (by increasing gastric secretions) expand the volume of gastric contents, but they do not alter the rate at which the contents are emptied. 3~ Aluminum hydroxide gel and propantheline both significantly prolong gastric emptying.275, 276 (2) 99mTc-DTPA/1-131 Hippuran." Renal Blood Flow and Renography Studies Cyclosporin A, a new immunosuppressive drug used most commonly in renal transplant patients, was evaluated in liver transplant patients to determine its effects upon renal function as measured by 99mTc-DTPA and I-!31 Hippuran. 277The results showed that the inherent nephrotoxicity of the drug may be difficult to distinguish from ischemic
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acute tubular necrosis and/or rejection in renal transplant patients. (3) 1-131
(7) 99mTc-DTPA: Diuretic-Augmented
Radionuclide Urography
The use of diuresis stimulated by furosemide in conjunction with 99mTcDTPA urography serves to help distinguish between certain types of obstructive vs. nonobstructive urinary tract dilatation and to evaluate all types of hydroureteronephrosis.Z82'283 (8) 99mTc-Microaggregated
Hippuran: Effective Renal Plasma Flow Determinations
Adverse effects of iodinated contrast agents upon renal function were investigated using serial effective renal plasma flow ( E R P F ) determinations. 278 As much as a 66% drop in ERPF was noted following administration of contrast media, although a return to baseline renal function occurred in nearly all patients within two weeks. The significance of this information to nuclear medicine is that renograms performed immediately following arterography or contrast enhanced C.T. scans should not be used "as 'baseline' studies for comparison with future examinations. ''278 (4) 99mTc-pertechnetate/I-131 Hippuran."
Albumin:
Liver/Spleen Imaging
Large focal defects were visualized on a liver/spleen scan in a patient who had received thorium dioxide (Thorotrast) 29 years previously. A cholangiocarcinoma had subsequently developed in the liver of this patient due to the presence of residual contrast material. 284 (9) 99mTc-Iron ascorbate: Brain imaging Dexamethasone therapy can diminish uptake of the radiopharmaceutical into areas of brain tumors, as discussed previously in the section on 99mTc-pertechnetate: Brain Imaging. 285 (10) 99mTc DTPA: Brain Imaging See discussion in (9). z86 The steroid effect on brain scans has been reported with virtually every "brain" imaging agent except 99mTc-gluceptate.
Renal Blood Flow and Renography Studies

While comparing the usefulness of two radionuclide renal function studies for evaluation of post renal transplant patients, the investigators noted three instances of acute rejection which were not identified by either procedure because of interference from the administration of high doses of furosemide. 279 (5) 1-125 Hippuran: Renography The effect of chlorpromazine (CPZ) pretreatment on ischemia of the kidney was studied in rabbits by using I-125 Hippuran renography. 28~Due to the decrease in vascular resistance induced by CPZ, renograms in treated animals returned to normal faster after unclamping of the renal artery than did the untreated. group. The significance of this investigation is the extrapolation of results to the transplantation clinic, where high vascular resistance in donated kidneys (after ischemic damage) is a problem. (6) 99m Tc-DTPA: Renal Function Studies A decrease in renal function on a 9 9 m T c - D T P A study was observed in a patient who had abused Darvon Compound, a phenacetin-containing drug, for many years. 281
(11 ) 99m Tc-Gluceptate: Brain Imaging

Chemotherapeutic neurotoxicity following therapy with cyclophosphamide, adriamycin, vincristine, and actinomycin D, was suspected as the cause for a "patchy increased activity in a serpiginous pattern" seen on a brain scan in a 29 mo old child] 87 (12) In-111 DTPA: Cisternography Therapy with acetazolamide (Diamox) resulted in a false positive cisternogram characteristic of normal pressure hydrocephalus. Inhibition of carbonic anhydrase by Diamox decreases the rate of cerebrospinal fluid (CSF) production by the choroid plexus which then indirectly alters CSF kinetics. In this case ventricular filling was evident on the scan. 288
(13) In-113m: Placental Scanning

ln-1 13m, which was used for placental scanning, normally remains within the vasculature bound to the plasma protein,
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transferrin. However, Richards et al. report that in 2 of 100 patients who received this radionuclide, the resultant images showed marked renal accumulation. The authors hypothesize that the In-I 13m was displaced from transferrin by iron, which the women had been taking orally during their pregnancy, with subsequent excretion of the radiotracer via the kidneys. 289 (14) I n - l l l Platelets: Thrombus Localiza-
normal spleen. From the data presented, the test appears to be useful for ruling out splenic involvement in patients with Hodgkins's disease. (18) 99m Tc-Sulfur Colloid: Gastroesopha-
tion In one clinical study and one animal study no interference with the affinity of In-1 1 1 platelets for thrombi was noted following heparin administration. 29~ The effect of aspirin therapy was also looked at in two patients, and this drug did not apparently alter the incorporation of In-1 1 1 platelets onto the surface o f clots. 290,291 (15) ln-l l l Leukocytes: Inflammatory Process Localization Investigators at the University of Utah have observed a failure of In-I 1 1 leukocytes to accumulate at sites of infection in patients on long term antibiotic therapy, although this has not been confirmed by controlled studies. 292 (16) Xenon-133 in saline: Regional BloodFlow Measurements Benzyl alcohol, which is used as a bacteriostat in some radiopharmaceuticals, is a known vasodilator and therefore could potentially alter the results of regional blood flow measurements. Therefore it should be avoided in radiopharmaceuticals used for such purposes. 293 (t7) Cr-51 Red Blood Cells: Spleen Imaging Osadchaya et al. studied the changes in splenic size in response to adrenaline, as monitored by scintigraphic methods, to determine if this method may serve as a diagnostic test for staging of Hodgkin's disease, i.e. for identifying splenic involvement. 294 The mean decrease in splenic size was significantly less in the Hodgkins patients with known splenic involvement compared to patients with a
geal Reflux Studies The effect of bethanechol in patients with esophageal reflux was evaluated using the technique of dynamic esophageal scintigraphy. The drug improved esophageal transit and clearance. 295Gastroesophageal scintigraphy has also been used for the quantitative estimation of reflux before and after therapy with an antacid as well as an antacid-alginate preparation (Gaviscon). 296 These products reduced reflux, whereas atropine, an antagonist of bethanechol, increased reflux when measured by this radionuclide method. 296 (19) 99mTc Sulfur Colloid: Hepatic Perfusion Scintigraphy In patients with neoplastic liver disease, 99mTc-sulfur colloid has been used by some clinicians to evaluate and monitor hepatic perfusion in patients receiving 5-fluorodeoxyuridine infusion therapy. This arterial liver perfusion scintigraphy allows for determination of the "position and patency of a catheter, the distribution of flow, occlusion of the hepatic artery, and extravasation. ''297 (20) 99roTe-Sulfur Colloid." GI Bleed Scintigraphy GI bleed scintigraphy using 99mTcsulfur colloid is now recognized as a safe, noninvasive, yet accurate means for localizing sites of hemorrhage in the lower gastrointestinal tract. Alavi and McLean report the use of this technique for monitoring the effectiveness of vasopressin in controlling GI hemorrhage. 298 (21) K-40: Whole-body Potassium Measurements Measurements of changes in body potassium as a result of diuretic (antihypertensive) therapy was accomplished using K-40 in 18 patients taking hydrochlorothiazide 50 mg twice daily and in 19 patients receiving hydrochlorothiazide 25 mg plus triamterene 50 mg twice
210
daily. 299 T h e f o r m e r t h e r a p y group had a significantly decreased total body potassium over the s i x - m o t r e a t m e n t period, whereas the l a t t e r group did not. (22) 99mTc-Microspheres: Regional Myo-
cardial Blood Flow

T h e r a d i o a c t i v e microsphere technique was used to e x a m i n e the effects of coron a r y occlusion and subsequent proprano1ol a n d o u a b a i n a d m i n i s t r a t i o n on regional m y o c a r d i a l blood flow in dogs. A t a dose of 1 m g / k g , propranolol increased flow to ischemic a r e a s of myoc a r d i u m and decreased flow to n o r m a l areas. T h e a d m i n i s t r a t i o n of o u a b a i n to dogs who had a l r e a d y received proprano1ol increased blood flow even further to ischemic zones. 3~176 (23) 1-125 meta-iodobenzylguanidine (m-
lorothiazide upon the biodistribution of several r a d i o p h a r m a c e u t i c a l s was syst e m a t i c a l l y investigated by Chervu et al. 3~ Modifications in distribution were found with all drugs, b u t details are lacking since only an a b s t r a c t is currently a v a i l a b l e for review.
CONCLUSION
IBG): Myocardial and Adrenal Studies

T h e u p t a k e of m I B G into dog m y o c a r d i u m and a d r e n a l m e d u l l a was a l t e r e d to varying degrees by the a d m i n i s t r a t i o n of reserpine, d e s m e t h y l i m i p r a m i n e , and 6 h y d r o x y d o p a m i n e . 3~ (24) Various radiopharmaceuticals: Biodis-
A n u n d e r s t a n d i n g of the d r u g s which modify r a d i o p h a r m a c e u t i c a l biodistribution, as well as the m e c h a n i s m t h r o u g h which these interactions occur, should benefit both the physician and the p a t i e n t by (a) avoidance of misdiagnoses, (b) i m p r o v e m e n t of diagnostic methods with approp r i a t e p h a r m a c o l o g i c intervention, and (c) use of sophisticated scintigraphic techniques to monitor responses to drug t h e r a p y . This p a p e r has a t t e m p t e d to s u m m a r i z e most of the c u r r e n t l y known r a d i o p h a r m a c e u t i c a l - d r u g interactions which can affect p a t i e n t diagnosis and m a n a g e m e n t by physicians and other medical personnel.
ACKNOWLEDGMENT
tribution Studies
T h e influence of multiple c o m m o n l y used m e d i c a t i o n s including lithium carbonate, c o u m a r i n , propylthiouracil, phenobarbital, digoxin, phenytoin, penicillin, propranolol, indomethacin, tapazole, m e t h y l d o p a , furosemide, and hydroch-
Portions of the introduction and of Tables 1-5 (without references) have been published previous in Advances in Radiopharmacology, LG Colombetti (ed), International Association of Radiopharmacology, Chicago, IL, 1981. They are reprinted here by permission of the editor. The authors would like to acknowledge the assistance of Victor J. Stathis, James A. Ponto, Leslie A. Hladik, Kay L. Hicks, and Elva G. Giron in the preparation of this manuscript.
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Drug-Induced Changes in the Biologic Distribution of Radiopharmaceuticals

William B. Hladik III, Karl K. Nigg, and Buck A. Rhodes

DRUG INDUCED CHANGES IN BIODISTRIBUTION

Table 1. Examples of RadiopharmaceuticaI-Drug Interactions Mediated Via a Proposed

9. 99mTc-phosphates 10. 99mTc-sulfur colloid

108, 109, 1 1 2 118 133-136

perfusion perfusion perfusion perfusion perfusion

HLADIK, NIGG, AND RHODES

53. 99mTc-sulfur colloid 54. 99mTc-sulfur colloid 55. K - 4 0 56. 99mTc-microspheres

296 298 299 300

DRUG INDUCED CHANGES IN BIODIS,FRIBU,rlON

Radiopharmaceutical Involved in Interaction 1. 2. 3. 4. 5. 6. 99mTcO4 99mTcO 4 99mTc-phosphates 99mTc-phosphates 99m,Fc-phosphates 99mTc-phosphates

Hepatobiliary Vascular pool MUGA Tumor/Abscess localization Tumor/Abscess localization

173 178 122, 180, 181 233 240-243

20. Ga-67 citrate 21. Ga-67 citrate

Tumor/Abscess localization ,rumor/Abscess localization

22. Ga-67 citrate 23. Ga-67 citrate 24. Ga-67 citrate

Tumor/Abscess localization ,rumor/Abscess localization ,rumor/Abscess localization

241 247 249,250

25. Ga-67 citrate

26. Ga-67 citrate

27. 99mTc-DTPA/I-131 Hippuran

HLADIK, NIGG, AND RHODES

Table 3. Examples of RadiopharmaceuticaI-Drug Interactions Mediated Via a Proposed Pharmacokinetic Mechanism*

DRUG INDUCED CHANGES IN BIODISTRIBUTION

Table 4. Examples of RadiopharmaceuticaI-Drug Interactions Mediated Via a Proposed Pharmaceutical Mechanism*

13. 99mTc-RBC's (99mTc04-) 14. T 1 - 2 0 1 chloride

Table 6. Examples of RadiopharmacauticaI-Drug Interactions Mediated Via an Unidentified Mechanism*

HLADIK, NIGG, AND RHODES

14-16, 33, 34, 39-42

Excess iodine uptake, dilution of body iodide pool

14, 16, 19, 22, 35, 36

HLADIK, NIGG, AND RHODES

Sedatives, Tranquilizing Agents (Meprobamate, Morphine)

Miscellaneous Agents Na Nitroprusside

Up to one wk following cessation of therapy

DRUG INDUCED CHANGES IN BIODISTRIBUTION

Adrenal and Gonadal Steroids; ACTH (Acthar, HP Acthar Gel)

HLADIK, NIGG, AND RHODES

DRUG INDUCED CHANGES IN BIODISTRIBUTION

HLADIK, NIGG, AND RHODES

DRUG INDUCED CHANGES IN BIODISTRIBUTION

HLADIK, NIGG, AND RHODES

DRUG INDUCED CHANGES IN BIODISTRIBUTION

AND XENOX-133 GAS" VENTILATION AND PERFUSION STUDIES OF MULTIPLE ORGANS

HLADIK, NIGG, AND RHODES

DERIVATIVES: HEPATOBILIARY IMAGING

DRUG INDUCED CHANGES IN BIODISTRIBUTION

(Sn+2-99mTcO4-RBC): IMAGING OF THE VASCULAR POOL

HLADIK, NIGG, AND RHODES

DRUG INDUCED CHANGES IN BIODISTRIBUTION

HLADIK, NIGG, AND RHODES

DRUG INDUCED CHANGES IN BIODISTRIBUTION

HLADIK, NIGG, AND RHODES

DRUG INDUCED CHANGES IN BIODISTRIBUTION

HLADIK, NIGG, AND RHODES

(7) 99mTc-DTPA: Diuretic-Augmented

Hippuran: Effective Renal Plasma Flow Determinations

Renal Blood Flow and Renography Studies

(11 ) 99m Tc-Gluceptate: Brain Imaging

(13) In-113m: Placental Scanning

DRUG INDUCED CHANGES IN BIODISTRIBUTION

HLADIK, NIGG, AND RHODES