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Pharmacogenetics

by Daniel A. Hussar, PhD

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 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 see Figure: Genetic, environmental, and developmental factors that can interact, causing variations in drug response among patients.).

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.

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

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • ANECTINE, QUELICIN
  • No US brand name
  • PLAVIX
  • LANIAZID
  • ARALEN
  • IMURAN
  • COUMADIN
  • TEGRETOL

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