DRUG METABOLISM

Drug Pharmacokinetics/Metabolic Profiles

Dr. Hira Choudhury

Lecturer, Department of Pharmaceutical Technology, School of Pharmacy
HiraChoudhury@imu.edu.my (ext. 1262)
 Stereoselective metabolism
 •Drug Metabolic Profiles :
 • Warfarin
 • Propranolol
 • Paracetamol / Acetaminophen
 • Ethanol
Schematic representation of pharmacokinetics and pharmacodynamics
.

Pharmacokinetics represents
Absorption, Distribution,
Metabolism, and Elimination
of drugs from the body.

Pharmacodynamics describes
the interaction of drugs with
target tissues.

Holland-Frei Cancer Medicine. 6th edition. Kufe

DW, Pollock RE, Weichselbaum RR, et al., editors.
Hamilton (ON): BC Decker; 2003.
 • Drugs are prescribed in racemates (both enantiomers).
 • Enantiomers are optically active.

Enantiomers may be metabolised differently (route and rate of

metabolism)

Example : Warfarin, propanolol, ibuprofen

 DRUG METABOLIC PROFILE OF WARFARIN

4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one
 WARFARIN
•Widely used oral anticoagulant with narrow therapeutic window
•Clinically avaialable as recemic mixture of R and S- warfarin
•S-enantiomer is 3 to 5 times more potent than R enantiomer.
•Undergoes extensive hepatic metabolism
•Stereo selective metabolism
• R- enantiomer :Reduction and oxidation by CYP 450
• S-enantiomer : Oxidattion by CYP 450
•S-enantiomer is eliminated faster than R –enantiomer
R-enatiomer : t1/2 = 59h
S-enatiomer : t1/2 = 33h
 MECHANISM & INDICATIONS OF WARFARIN
Mechanism of Action
Warfarin acts by antagonising the
antihemorrhagic effect of Vitamin K

It inhibits activation of vitamin K

dependent activation of coagulation
factors II, VII, IX and X

INDICATION:
Prophylaxis and or treatment of
venous thrombosis,
Pulmonary embolism
Thromboembolic complication
associated with artrial fibrilation
or cardiac valve replacement
METABOLISM & PHARMACOKINETIC PROFILE OF WARFARIN
Absorption Rapid and complete : (Oral bioavailability : nearly 100%)

Distribution Distributed in liver, kidney, lungs and spleen etc. It crosses

placenta (known as teratogen)
Protein binding Very high : 99% (mainly bind with albumin)
Metabolism Hepatic : primarily : CYP450 2C9 ;
Minor pathways : CYP2C19, 1A2, 3A4

Metabolized to inactive metabolite which excreated in bile

Onset of action Oral : 24 to 72 hours
Duration of Usually 2 to 5 days after single oral dose
action
Half Life 20 to 60 hours
Excreation Urine 92 % (primarily as metabolites)
METABOLISM OF WARFARIN
 METABOLIC PROFILE OF WARFARIN

Major urinary metabolites :

–Sulphate and glucuronide conjugates of hydroxy warfarins

•Factors affecting warfarin plasma levels :

-Induction of cytochrome P450
eg: phenobarbitone, rifampicin, carbamazepines
–Inhibition of cytochrome P450
•eg: cimetidine, ketoconazole, verapamil, amiodarone
–Displacement from albumin binding sites (since warfarin
is extensively bound to albumin)
•eg: phenybutazone
 DRUG METABOLIC PROFILE OF PROPRANOLOL

(RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol
 MECHANISM & INDICATIONS OF PROPANOLOL
Mechanism of action :

Competitively blocks response to beta1- and beta2-adrenergic

stimulation which results in decreases in heart rate, myocardial
contractility, blood pressure, and myocardial oxygen demand.

Therapeutic uses:

•Hypertension
•Angina
•Congestive heart failure
•Hyperthyroidism
METABOLISM & PHARMACOKINETIC PROFILE OF PRPPRANOLOL
Absorptioncccc Oral route : Rapid and complete

Distribution Vd : 4L/kg
Protein binding 90%
Metabolism Extensive first pass effect
Hepatic (CYP2D6, 1A2) to 4-OH propanolol (active)
Onset of action Oral : 1 to 2 hours

Duration of action Immediate release : 6-12 h

Extended release : 24-27 h

Elimination Immediate release formulation : 3-6 h

Half Life Extended release formulation : 8-10 h
Excreation Primary in urine (96-99%)
<1 % excreted in urine as unchanged drug
Stereoselective metabolism

–S-enantiomer : aromatic hydroxylation CYP450

–R-enantiomer : dealkylation CYP450

•Other metabolism pathways include :

–Glucuronidation
–Sulfation
METABOLISM OF PROPRANOLOL
DRUG METABOLIC PROFILE OF PARACETAMOL
MECHANISM OF ACTION AND INDICATION OF PARACETAMOL

Arachdonic acid

Paracetamol (X) Cyclooxygenase

Prostaglandin

Stimulate Swelling, redness,

Pain, increased in temperature

Recommended as antipyretic and analgesic

Absorption Mainly absorbed from small intestine

Distribution 1L/kg
Protein binding 10-25% at therapeutic dose ; 8-43% at toxic dose
Metabolism Subject to first pass metabolism
Primary hepatic metabolism
Onset of action Oral : <1 hour
IV: Analgesic : 5-10min or antipyretic : <30min
Duration of action analgesic : 4-6 h ; antipyretic : >6 h
Elimination Half Life 2-3 h

Excreation Urine (<5% unchanged)

60-80% as glucuronide metabolites
20-30% as sulphate metabolites
8% as cysteine and mercapturic acid metabolites
 ETHANOL

Ethanol rapidly crosses cell membranes and easily absorbed. When the
stomach is empty, peak blood ethanol levels are reached between 30-
90min after ingestion.

•
Sign and symptoms of alcohol intoxication :
–Slurred speech, incoordination, unsteady, memory impairment
 Rettie, A.E. and G. Tai, The pharmocogenomics of warfarin: closing in on
personalized medicine. Mol Interv, 2006. 6(4): 223-7

 Reza Mehvar and Dion R. Brocks, Stereospecific Pharmacokinetics and

Pharmacodynamics of Beta-Adrenergic Blockers in Humans.
J Pharm Pharmaceut Sci,2001.4(2): 185-200

 L.F. Prescott, Kinetics And Metabolism Of Paracetamol And Phenacetin.

Br. J. clin. Pharmac. (1980), 10, 291S-298S
“Live as if you were to die tomorrow. Learn as if you were to live forever.”
– Mahatma Gandhi

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