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Pharmacogenetics

Pharmacogenetics is concerned with the genetic variability of drug effects. Differences

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in genetic sequences that occur at a frequency of at least 1% are designated as

polymorphisms. Rare variants are observed in less than 1% of a population.
Polymorphisms may either influence the pharmacokinetics of a drug (A) or occur in the
target genes that mediate the therapeutic effect of drugs (B).

Genetic variants of pharmacokinetics.

Polymorphisms can occur in all genes that participate in the absorption, distribution,
biotransformation, and elimination of drugs. Subjects who break down a drug more
slowly owing to a genetic defect are classified as “slow metabolizers” or poor
metabolizers” in contrast to “normal metabolizers.” When delayed biotransformation
causes an excessive rise in plasma levels, the incidence of toxic effects increases, as
evidencedby the example of the immunosuppressants azathioprine and mercaptopurine.
Both substances are converted to inactive methylthiopurines by the enzyme thiopurine
methyltransferase (TMPT). About 10% of patients carry a genetic polymorphism that
leads to reduced TMPT activity and in < 1% enzyme activity is undetectable. As a result
of the diminished purine methylation, the plasma level of active drug rises and, hence, the
risk of toxic bone marrow damage rises. To avoid unwanted toxic effects, TMPT activity
can be determined in erythrocytes before therapy with mercaptopurine is started. In fact,
TMPT polymorphism is the first pharmacogenetic test to be introduced into clinical
practice. In patientswith complete TMPT deficiency, the dose of azathioprine should be
reduced by 90%.

Other genetic variants of drug metabolism may have a similar impact: a defect of
Nacetyltransferase 2 impedes the N-acetylation of diverse drugs, including isoniazid,
hydralazine, sulfonamides, clonazapam, and nitrazepam. “Slow acetylators” (50–60%
of the population) are more likely than “fast acetylators” to develop toxic reactions and
neuropathy. A genetic defect of the cytochrome P450 isozyme CYP2D6 (originally
described as debrisoquine–sparteine polymorphism) occurs in ~8% of Europeans and
results in delayed elimination of a various drugs, including metoprolol, flecainide,
nortriptyline, desipramine, and amitriptyline.

Genetic variants of pharmacodynamics.

Genetic polymorphisms can also involve genes that directly or indirectly mediate the
effects of drugs and, hence, alter pharmacodynamics (B). In these cases, the biological
effects of a drug are changed, rather than its plasma levels. The genetic variants of β-
adrenoceptors provide an example. For instance, hypertensive patients carrying an
arginine at amino acid position 389 of the β1-receptor respond to metoprolol with a
more marked fall in blood pressure than do patients carrying a glycine residue at this
position. Since β1-blockers have a relatively large margin of safety and, as a rule, dosage
is determined by the observed effect, genotyping of patients prior to administration of β-
blockers would appear unnecessary.

Future research may be expected to identify numerous genetic polymorphisms in the

target molecules of drugs. A genetic examination before the start of drug therapy will be

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a sensible precaution, particularly when drugs with a narrow margin of safety or a long
half-life are to be used on a fixed dosage regimen.

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