Pharmacogenetics involves variations in drug response due to genetic makeup.

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 3: Concepts in Pharmacotherapy: 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 azathioprineSome Trade Names
IMURAN
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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, carbamazepineSome Trade Names
TEGRETOL
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, clopidogrelSome Trade Names
PLAVIX
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, warfarinSome Trade Names
COUMADIN
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), 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 Fig. 1: Concepts in Pharmacotherapy: Genetic, environmental, and developmental factors that can interact, causing variations in drug response among patients.).

Table 3
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Examples of Pharmacogenetic Variations Variation Incidence Effects Acetylation, fast — Need for higher or more frequent doses of drugs that are acetylated (eg, isoniazidSome Trade Names INH NYDRAZID Click for Drug Monograph ) 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 isoniazidSome Trade Names INH NYDRAZID Click for Drug Monograph , peripheral neuritis; with hydralazineSome Trade Names APRESOLINE Click for Drug Monograph or procainamideSome Trade Names PROCAN SR PRONESTYL Click for Drug Monograph , 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 CYP2C19 genetic polymorphisms 30% in one study Common among East Asians Reduced enzymatic activation of clopidogrelSome Trade Names PLAVIX Click for Drug Monograph , resulting in reduced antiplatelet effect and high risk of thrombosis in high-risk patients G6PD deficiency 10% of black males High prevalence in people of Mediterranean descent With use of oxidant drugs, such as certain antimalarials (eg, chloroquineSome Trade Names ARALEN Click for Drug Monograph , primaquineSome Trade Names No US trade name Click for Drug Monograph ), increased risk of hemolytic anemia Genetic polymorphisms of CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) — Increased action of warfarinSome Trade Names COUMADIN Click for Drug Monograph ,* 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 carbamazepineSome Trade Names TEGRETOL Click for Drug Monograph , including serious dermatologic reactions (eg, Stevens-Johnson syndrome) Plasma pseudocholinesterase deficiency About 1/1500 people Decreased succinylcholineSome Trade Names ANECTINE QUELICIN Click for Drug Monograph inactivation With conventional succinylcholineSome Trade Names ANECTINE QUELICIN Click for Drug Monograph 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 warfarinSome Trade Names COUMADIN Click for Drug Monograph dosage.

Fig. 1
Genetic, environmental, and developmental factors that can interact, causing variations in drug response among patients.

Last full review/revision January 2010 by Daniel A. Hussar, PhD

Content last modified February 2012