Vermont E.

Arvesu, RPh

Plasma Protein Binding

Reversible interaction of drugs with proteins

in plasma blood and tissue constituents
- weak bonds (van der Waals, hydrogen
ionic bonds)
- rates of drug binding and release are very
fast

Binding proteins as drug reservoirs

- sequester drugs in a non-diffusible form
and slow down their transfer out of the vascular
compartment

Plasma Protein Binding

- as FREE DRUG concentration decreases due to
metabolism or excretion, the BOUND DRUG
dissociates from the protein maintaining FREE
DRUG concentration

Major Drug Binding Proteins

Albumin
- at least 6 binding sites, 2 very tightly and
specifically bind long chain FA, 1 for acidic
drugs
- 50-60% of plasma proteins
- 1 agent responsible for maintaining osmotic
pressure of the blood, and for transport of
FA, hormones, enzymes and drugs.
- Drugs which bind at the same site can
displace each other respectively
- decreased concentration in liver and renal
diseases

Major Drug Binding Proteins

1-acid glycoprotein
- 1 binding site selective for basic drugs
- increased concentration in RA and post MI

Lipoproteins (LDLs and HDLs)

- LDL Low Density Lipoproteins

bad cholesterol
- HDL High Density Lipoproteins

good cholesterol

Lipoproteins (LDLs and HDLs)

Lipoproteins (LDLs and HDLs)

Metabolism

Irreversible conversion of a drug to a

different substance in vivo by enzymatic
catalysis or biochemical transformation of
drug to metabolic products
(BIOTRANSFORMATION)
a. body deactivates drugs
b. less pharmacologic activity than the
parent compound
- polar and more water-soluble LESS drug
is REABSORBED
c. Pharmacologically active
- PRODRUGS (preferred compound than
the original drug)

Metabolism
- e.g., Phenacetin from Acetaminophen;
Oxazepam from Diazepam

d. More toxic than the parent compound

Major biotransformation organ: LIVER

Major biotransformation substructure:

hepatic microsomes

Quantitatively altered by drug interactions

metabolism = Induction of Enzyme Activity

metabolism = Competitive Inhibition

Presystemic Metabolism
(First Pass Effect)
MOUTH
Enzymes and normal oral flora

STOMACH
Acidic pH

Small Intestine
Enzymes and Intestinal flora

Presystemic Metabolism
(First Pass Effect)
Gut wall and blood
leading to the liver
enzymes
Liver microsomes

bioavailability for
systemic circulation

Hepatic Biotransformation
PHASE I REACTIONS
- Convert lipophilic molecules into more
polar molecules by introducing or
unmasking a polar functional group
- catalyzed by the cytochrome P450
system (microsomal mixed function
oxidase)

- metabolites are sufficiently polar and

can be excreted

Phase I reactions

OXIDATION
- addition of O2 or removal of H
REDUCTION
- addition of H or removal of O2
Hydrolysis
- addition of H2O and break down of the
molecule

Phase II reactions
- Occur when the metabolites from Phase I are
too lipophilic to be retained in the kidney
tubules
- Result to polar, more water-soluble
compounds that are most often
therapeutically inactive

Glucuronidation
- MAIN conjugation reaction
- natural substrates are bilirubin and thyroxine

Phase II reactions

Acylation
- with acetyl group
Glycine
- glycine addition

Sulfate
- sulfate addition

Pharmacogenetics

Study the effects that genetic differences

have on the metabolism of certain drugs

Type

Genetic
Alteration

Selected
Examples

Clinical
Manifestation

Slow vs. Rapid

Acetylation

N- acetyl
transferase

INH,
Hydralazine,
Procainamide

Toxicity

Slow vs. Rapid

Hydrolysis

Pseudocholin
Esterase

Succinylchloride

Toxicity

Glucose-6phosphate
dehydrogenase
(G6PD)

G6PD

Primaquine,
Aspirin, Fava
beans

Hemolysis

Uncontolled
Calcium release

heterogenous

General
Anesthetics,
Neuromuscular
blocking agents

Malignant
Hyperthermia

Excretion

Irreversible transfer of the intact drug

from the blood to the urine or other
excretory compartments
- MAJOR organ or site of excretion: KIDNEY
- Functional unit: nephron

Excretion

3 Major Processes of Excretion

1.

Glomerular Filtration
- ALL low MW molecules are filtered out of
the blood
- normal filtration rate (GFR) = 100-130
ml/min
- often measured by the RENAL CLEARANCE
of INULIN
- Inulin is readily filtered in the glomerulus
and is NOT subject to tubular secretion or
reabsorption

3 Major Processes of Excretion

2. Tubular Secretion
- proximal tubule: reabsorption of H2O and
ACTIVE secretion of some weak electrolytes
esp. WEAK ACIDS
- requires ACTIVE transport
3. Tubular Reabsorption
- distal tubule: PASSIVE excretion and
reabsorption of LIPID soluble groups

3 Major Processes of Excretion

Hemodialysis

ARTIFICIAL kidney therapy used in renal

failure removes toxic waste material
normally removed by the kidneys from the
patient blood

Blood is diverted externally and allowed to

flow across a SEMIPERMEABLE membrane that
is bathed with an aqueous ISOTONIC solution

Nitrogenous waste products will diffuse from

the blood and then eliminated

Hemodialysis

Biliary Excretion

Liver secretes 0.25-1.0 L of bile daily

Drugs containing polar and lipophilic groups

(MW>300) and their metabolites are excreted
by the liver into the bile.

Jaundice

Pulmonary Excretion

LUNGS: major organ of excretion for gaseous

and volatile substances

Salivary Excretion

Dependent on pH partition and protein

binding

More useful in determining drug

concentration in the plasma since the salivafree plasma ratio is fairly constant