Polymorphisms of genes can affect drug therpay in three ways: polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in genes encoding for drug transporters, and polymorphisms in genes encoding for drug targets.
Polymorphisms in Genes for Drug-Metabolizing Enzymes
Polymorphisms in the drug-metabolizing enzymes represent the first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. The major phase I enzymes are the CYP superfamily of isoenzymes. N-acetyltransferase, uridine diphosphate glucuronosyltransferase (UGT), and glutathione S-transferase are examples of phase II metabolizing enzymes that exhibit genetic polymorphisms. Thiopurine S-methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD) are examples of nucleotide base-metabolizing enzymes.
Polymorphisms in Drug Transporter Genes
Certain membrane-spanning protein facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood-brain barrier, and drug uptake into target cells. Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action.
Polymorphisms in Drug Target Genes
Genetic polymorphisms occur commonly for drug target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drug target genes may work in concert with genes that affect pharmacokinetic properties (i.e., genes for drug transporters and drug-metabolizing enzymes) to contribute to overall drug response. These drug targets include receptors, enzymes, intracellular signaling proteins, and ion channels.
Numerous genes have been correlated with disease outcomes, and many of these have been found subsequently to influence response to pharmacologic disease management. These gene-drug response associations often occur despite the lack of a direct effect on pharmacokinetic or pharmacodynamic drug properties.