Pharmacogenomics

Abstract

Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.

Figure 1:

A. In some instances, variants in single genes (often those determining pharmacokinetics, as highlighted in Figure 2) have large effect sizes, and distinct metabolizer phenotypes can be predicted: poor metabolizers with two loss of function alleles, intermediate metabolizers with one functional allele, normal metabolizers with two functional alleles, and ultrarapid metabolizers with duplications or other variants conferring increased metabolic activity. In this situation, distinct genotype-dependent differences in drug response may be seen, although there may still be overlap. B. When variants in many pharmacogenes contribution to variability in drug action, the distribution of drug responses is not polymodal as (A), but rather a continuum.

Figure 2:

Two scenarios under which single variants in key pharmacokinetic genes can produce very large effects due to variability in active drug concentration. When a prodrug (top) such as codeine requires bioactivation to generate its active metabolite (morphine), increased enzymatic function can lead to morphine toxicity and decreased enzymatic function can lead to decreased analgesia. Similarly, variability in metabolism of an active drug such as azathioprine (bottom) can modulate risk of serious drug toxicity.