FACTOR AFFECTING DRUG METABOLISM

GENETIC POLYMORPHISM

- Genetic differences can influence

o Amounts
o & efficiency of metabolic enzymes
- Response to drugs  varies bet. individual
o Variation usually shows  Gaussion distribution (dumbbell – normal distribution)
o Bt sm drug responses show  Discontinuous variation
o CONSEQUENCES : mayb
1. Therapeutic failure or an
2. Adverse drug reaction

Continuous variation Discontinuous variation

No distinct categories Distinct categories

Tends to b QUANTITATIVE Tends to b QUALITATIVE

Controlled by a lot of genes Controlled by a few genes

Strongly influenced by environment Unaffected by environment

- Polymorphism may lead to 3 phenotypes:

1. EXTENSIVE metabolizer  have functional enzyme activity
2. INTERMEDIATE metabolizer  have diminished enzyme activity
3. POOR metabolizer  have little or no enzyme activity

Example:

- Metabolism via acetylation

o Acetylation with Acetyl-CoA is either fast or slow
o Genetic differences in N-acetyltransferase activity
o FAST acetylators  Eskimo & Asian ppl
o SLOW acetylators  Egyptians & sm Western European

Example drug: isoniazid used for tuberculosis

Slow acetylators Fast acetylators

T1/2 (minutes) 140-200 minutes 45-80 minutes

Plasma accumulation Higher Lower

Cure rate (depends on drugs)
ADR
Higher Lower
More adverse side effects: More associated:
- Peripheral neuritis - Liver damage
- Drug-drug interaction - Hepatitis
with isoniazid due to:
- Rapid formation of
acetylhydrazine