The activity of drug-metabolizing enzymes often varies widely among healthy people, making metabolism highly variable. Drug elimination rates vary up to 40-fold. Genetic factors and aging seem to account for most of these variations.
Pharmacogenetic variation (eg, in acetylation, hydrolysis, oxidation, or drug-metabolizing enzymes) can have clinical consequences (see table Examples of Pharmacogenetic Variations). For example, if patients metabolize certain drugs rapidly, they may require higher, more frequent doses to achieve therapeutic concentrations; if patients metabolize certain drugs slowly, they may need lower, less frequent doses to avoid toxicity, particularly of drugs with a narrow margin of safety. For example, patients with inflammatory bowel disease who require azathioprine therapy are now routinely tested for thiopurine methyltransferase (TPMT) genotype to determine the most appropriate starting dose for drug therapy. Most genetic differences cannot be predicted before drug therapy, but for an increasing number of drugs (eg, carbamazepine, clopidogrel, warfarin), changes in effectiveness and risk of toxicity have been specifically associated with certain genetic variations. Also, many environmental and developmental factors can interact with each other and with genetic factors to affect drug response (see figure Genetic, environmental, and developmental factors that can interact).
Examples of Pharmacogenetic Variations
Variation |
Incidence |
Effects |
|
Acetylation, fast |
— |
Need for higher or more frequent doses of drugs that are acetylated (eg, isoniazid) to produce the desired therapeutic response |
|
Acetylation, slow (drug inactivation by hepatic N-acetyltransferase) |
About 50% of the US population |
Increased susceptibility to adverse effects of drugs that are acetylated (eg, with isoniazid, peripheral neuritis; with hydralazine or procainamide, lupus) |
|
Aldehyde dehydrogenase-2 deficiency |
About 50% of Japanese, Chinese, and other Asian populations |
With alcohol ingestion, marked elevations of blood acetaldehyde, causing facial flushing, increased heart rate, diaphoresis, muscle weakness, and sometimes catecholamine-mediated vasodilation with euphoria |
|
CYP2C9 genetic polymorphisms |
30% in one study More common among East Asians |
Reduced enzymatic activation of clopidogrel, resulting in reduced antiplatelet effect and increased risk of thrombosis in high-risk patients |
|
G6PD deficiency |
10% of black males Higher prevalence in people of Mediterranean descent |
With use of oxidant drugs, such as certain antimalarials (eg, chloroquine, primaquine), increased risk of hemolytic anemia |
|
Genetic polymorphisms of CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) |
— |
Increased action of warfarin,* increasing risk of bleeding events |
|
HLA-B*1502 |
1 to 6/10,000 in countries with mainly white populations In some Asian countries, about 10 times higher |
Increased risk of adverse reactions to carbamazepine, including serious dermatologic reactions (eg, Stevens-Johnson syndrome) |
|
Plasma pseudocholinesterase deficiency |
About 1/1500 people |
Decreased succinylcholine inactivation With conventional succinylcholine doses, prolonged paralysis of respiratory muscles and sometimes persistent apnea requiring mechanical ventilation until the drug can be eliminated by alternate pathways |
|
* In one study, variations in CYP2C9 or VKORC1 genes accounted for about 40% of variance in warfarin dosage. |
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