DRUG METABOLISM

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
 DRUG METABOLISM

Mechanism by which the body terminates

the action of some drugs
In some cases, it serves to activate
prodrugs
1. Active ----- inactive (readily excreted
by the kidneys)
2. Active ----- active metabolites
3. Inactive --- active
(Prodrug)
 DRUG METABOLISM

TYPES OF METABOLIC REACTIONS

PHASE I
Non-synthetic reactions
Converts the parent drug to a more polar
conjugate (water soluble) or more reactive
product
Introducing/inserting/unmasking a polar
functional group
OH, SH, NH2
 DRUG METABOLISM

TYPES OF METABOLIC REACTIONS

PHASE I
1.Oxidation
2.Reduction
3.Deamination
4.Hydrolysis
 DRUG METABOLISM

TYPES OF METABOLIC REACTIONS

PHASE II
Synthetic reactions
Endogenous substrate is conjugated to
the parent drug to make it more polar
 DRUG METABOLISM

TYPES OF METABOLIC REACTIONS

PHASE II
1. Glucoronidation-glucoronic acid
2. Acetylation-acetyl CoA
3. Sulfation
4. Methylation
5. Glycine conjugation-glycine
6. Glutathione conjugation
7. H 2 0 conjugation
 DRUG METABOLISM

PHASE I ------- PHASE II (most drugs)

PHASE II ------- PHASE I (other drugs)
Isoniazid Acetylation ------- hydrolysis
 DRUG METABOLISM

PENICILLIN
Maybe metabolized by gastric fluid
Must be given 2 hours before meals
if given through the oral route
OTHER DRUGS METABOLIZED
Gastric acid
Penicillin
Gastric and digestive enzymes
Insulin
Intestinal wall enzymes
Epinephrine
 DRUG METABOLISM

LIVER
Most important organ for drug metabolism
Smooth endoplasmic reticulum (SER)
contains high concentration of PHASE I
enzymes
Mixed function oxidases
Activity of these enzymes require
NADPH (reducing agent)
Molecular form of oxygen
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
A. GENETIC FACTORS
1. HYDROLYSIS OF ESTERS
Succinylcholine
Ester that is metabolized by plasma
choline esterase
In most individuals, the process occurs
rapidly
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
A. GENETIC FACTORS
1. HYDROLYSIS OF ESTERS
Duration of action is 5 minutes
In 1/2500
Abnormal form of this enzyme
Neuromuscular paralysis may last for hours
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
A. GENETIC FACTORS
2. ACETYLATION OF AMINES
Isoniazid (INH)
Amines such as hydralazine, and
procainamide
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
A. GENETIC FACTORS
2. ACETYLATION OF AMINES
SLOW ACETYLATORS
Individuals deficient in acetylating
capacity
Prolonged or toxic responses to normal
doses of this drug
 DRUG METABOLISM
DETERMINANTS OF
BIOTRANSFORMATION RATE
A. GENETIC FACTORS
3. OXIDATION
Dextrometorphan, metoprolol and some
tricyclic antidepressants
Oxidation by P450 isoenzymes are
genetically predetermined
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
Individual differences
Diet and environmental factors
Charcoal inhibits the effect of the
drug
Grapefruit juice increases the
amount
of drug in the body
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
Individual differences
Age and sex
Drug metabolites differ in young and
old
Males metabolize drugs faster than
females
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE

Disease affecting drug metabolism

Hyperthyroidism
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
B. OTHER DRUGS
1. ENZYME INDUCTION
Increase rate of synthesis of the enzyme
Reduce the rate of degradation of the
enzyme
May also induce self metabolism of the drug
May also induce metabolism of other drugs
and reduce its effects
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
B. OTHER DRUGS
1. ENZYME INDUCTION
Enzyme inducers
Phenobarbital
Carbamazepine + drug = decreased
effects
Phenytoin
Rifampicin
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
B. OTHER DRUGS
2. ENZYME INHIBITION
Inhibit CP450
Metabolism of the drug is diminished
Increase effect of the drug
 DRUG METABOLISM

DETERMINANTS OF
BIOTRANSFORMATION RATE
B. OTHER DRUGS
2. ENZYME INHIBITION
Enzyme inhibitors
Amiodarone
Cimetidine
Ketoconazole + drug = increased effect
Ritonavir
Furanocoumarin
 DRUG METABOLISM

TYPES OF DRUG INTERACTION

MECHANISM
Altered absorption
Cholestyramine inhibits the effect of
digoxin when combined with it
Altered metabolism
Affects drug action
 DRUG METABOLISM

TYPES OF DRUG INTERACTION

MECHANISM
Altered plasma binding protein
Altered excretion
Probenecid inhibits the secretion of
acids
Penicillin inhibits the excretion of
probenecid
 DRUG METABOLISM
DRUG INTERACTION
1. ADDITIVE
1+1=2
Response elicited by combined drugs is
equal
to the combined response of the
individual drugs
Sedative + ethanol
 DRUG METABOLISM

DRUG INTERACTION
2. SYNERGISTIC
1+1=3
Response elicited by combined drugs is
greater than the combined responses of
each individual
Penicillin G removes the cell wall
Gentamicin inhibits production of
protein
 DRUG METABOLISM

DRUG INTERACTION
3. POTENTIATION
0+1=2
Drug which has no effect enhances the
effect of the second drug
Cimetidine + anticoagulant
( enhances the anticoagulation)
 DRUG METABOLISM

DRUG INTERACTION
4. ANTAGONISM
1+1=0
Drug inhibits the effect of another drug
Heparin + protamine