ABSTRACT
It is well recognized that there is wide interindividual variability in drug response. Given
the same dosage of a drug, some patients experience complete remission, some fail to
respond, and others experience severe toxicities. These differences in drug response are
influenced by many factors, including demographics (age, sex, ethnicity), organ function
and comorbidities, environmental exposures (diet, carcinogen exposure, drug inter-
actions), and genetics (Fig. 1). In general, genetic factors are estimated to account for 15%
to 30% of interindividual variability in drug response, but for certain drugs, genetic
factors could explain up to 95% of this variation (1-4). The term “pharmacogenetics” was
coined almost 50 years ago to refer to the role of inherited genetic variation in prediction
of drug response (5). Earlier pharmacogenetic studies focused on pharmacokinetics, or the
way the body metabolizes a drug and controls the amount of the drug at the site of action,
which includes the absorption, distribution, metabolism, and excretion (ADME) of the
drug. Almost all of the classic examples of pharmacogenetics (e.g., NAT2, CYP2D6,
CYP2C19, TPMT, UGT1A1) have come from studies of pharmacokinetics. This area of
pharmacogenetics, related to pharmacokinetics, continues to attract much attention, with
growing research in drug transporter and metabolizing enzymes. The second component
of pharmacogenetics is pharmacodynamics, which involves the mechanisms of drug action.
With the completion of the human genome, the international Hapmap project, and rapid
advance of high-throughput whole-genome technologies, the field of pharmacogenetics has
been undergoing a steady evolution from the study of monogenic traits to that of polygenic
traits, and from small-scale candidate approach to comprehensive and whole-genome
approaches. The newer term “pharmacogenomics” reflects such an evolution, which often
involves large-scale, genomewide analysis to identify genetic factors relevant to drug
response. However, these two terms are often used interchangeably.
