Polymorphisms related to pharmacotherapy include polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in drug transporter genes, and polymorphisms in drug target genes.
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. eTable 6-1 lists examples of polymorphic metabolizing enzymes and corresponding drug substrates whose plasma concentrations and pharmacologic effects may be altered as a consequence of genetic variation.
Polymorphisms in the CYP2D6 gene are the best characterized among all polymorphisms in genes for drug-metabolizing enzymes. For example, the presence of two defective alleles coding for CYP2D6 in PM (poor metabolizer) results in significant impaired ability to metabolize CYP2D6-dependent substrates. Depending on the importance of the affected CYP2D6 pathway to overall drug metabolism and the drug's therapeutic index, clinically significant side effects may occur in PMs as a result of elevated drug concentrations.
Conversely, if the polymorphisms in CYP2D6 genes significantly enhance the activity of the drug-metabolizing enzyme, large amount of drugs will be metabolized and as a result the serum concentraton and pharmacologic effect of the drug would probablely be significantly lower.
The therapeutic implication of CYP2D6 polymorphism is different if the substrate in question is a prodrug. In this case, PMs would not be able to convert the drug into the therapeutically active metabolite (if low CPY2D6 activity).
Polymorphisms in Drug Transporter Genes
Certain membrane-sparnning proteins 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.
Polymorphisms in drug transporters on gastrointestinal tract would affect the absorption of drugs. The role of drug transproters on gastrointestinal tract is to put the drug molecule back into GI lumen. So the activity of these drug transporters would significantly alter the bioavailability/absorption of the drug.
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. P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism.
Some drug are transported into bile or urine by drug transporters. So the polymorphisms in these transporters which result in significant change of the activity of the drug transporters would enhance or weaken the ability of these drug transporters's ability to excret the drug.
Drug Uptake by Target Cells
Even the drug could reach the therapeutic sites of action, efflux pumps (drug transporters) available on the surface of target cells could put the drug molecules back into extracellular environment, which prevent the pharmacologic effect of the drug if the drug's target receptors are inside the target cells.
Polymorphisms in Drug Target Genes
Genetic polymorphisms occur commonly for durg target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drugs could bind to enzymes, ion channels, and intracellular signaling proteins directly to produce pharmacologic effects, or they just only bind to the receptor and the after-binding (drug-receptor) process is altered by polymorphisms in enzymes, ion channels, and intracellular signaling proteins.
Receptor Genotypes and Drug Response
The beta1-adrenergic receptor gene (ADRB1) has been the primary focus of research into genetic determinants of responses to beta-adrenergic receptor antagonists in hypertension and cardiovascular disease. The polymorphisms in beta1-adregergic receptors causes pharmacologic (or even clinical) responses in different extent to its agonists and antagonists.
Enzyme Genes and Drug Response
Some drugs exert their clinical efficacy by affect enzymes which play some roles in the life of a cell. Polymorphisms in these enzymes therefore determine what degree of responsiveness they respond to these drugs. One example is the warfarin resistance, where there is a SNP in the VKORC1. Warfarin exerts its anticoagulant effects by inhibiting VKOR and thus preventing carboxylation of the vitamin K-dependent clotting factors II, VII, IX, and X. VKORC1 encodes for the warfarin-sensitive component of VKOR. Mutations in VKORC1 coding region cause rare case of warfarin resistance, with carriers of these mutations requiring either exceptionally high doses (>100 mg/wk) to achieve effective anticoagulation or failing to respond to warfarin at any dose (the mutated VKOR lose sensitivity to warfarin).
Genes For Intracellular Signaling Proteins, Ion Channels, and Drug Response
Cellular responses to many drugs are mediated through receptor-coupled guanosine diphosphate (GDP)-bound proteins also called G-proteins. Following receptor activation, the receptor couples to the G-protein, resulting in dissociation of GDP from the alpha subunit in exchange for guanosine triphosphate (GTP) and activation of the alpha, beta, and gamma subunits. The alpha subunit and beta-gamma subunit complex are released intracellularly and interact with various effectors to produce a cellular responses. Changes in the activity of G-proteins might influence response to agonists/antagonists which bind the receptors coupled with G-proteins.