Drug transporters and drug-metabolizing enzymes participate in the processes of absorption, disposition, metabolism and elimination, which influence the pharmacokinetics and pharmacodynamics of a new chemical entity (NCE). Therefore, understanding an NCE's potential as a substrate, inhibitor or inducer of a drug-metabolizing enzyme or transporter has become an essential element of risk assessment during drug discovery, development and regulatory review [1][2][3][4][5][6][7].
Drug metabolismDrugs are metabolized by Phase I and/or II enzymes in several organs, especially the liver, intestine and kidneys. The aim of drug metabolism is to increase the polarity and solubility of the molecule to enable its elimination. Phase I metabolic reactions introduce reactive and polar groups into the substrate NCE. Cytochrome P450 (CYP) enzymes integrate an oxygen atom into nonactivated hydrocarbons, resulting in either the introduction of hydroxyl groups or the N-, O-and S-dealkylation of substrates. Other Phase I enzymes include the flavin monooxygenases, monoamine oxidases and xanthine oxidase/aldehyde oxidase. Outcomes of Phase I metabolism include inactivation of the drug by production of pharmacologically inactive metabolites or generation of active metabolite(s). Phase II metabolic reactions include glucuronidation, sulfonation, methylation, acetylation and glutathione conjugation. Phase II enzymes include uridine-5 -diphospho-glucuronosyltransferases, sulfotransferases, glutathione S-transferases and N-acetyltransferases. Metabolites formed during Phase II reactions are not likely to be pharmacologically active.
Drug transportUptake and efflux transporters determine plasma and tissue concentrations of both endogenous and exogenous substances. The transporters are found in the small intestines, liver and kidneys, which are critical for drug absorption and elimination. They are also located in vital blood-tissue barriers such as the blood-brain and blood-placenta barriers. Solute carrier transporters facilitate the uptake of compounds into cells through facilitated diffusion or via cotransport with intracellular and/or extracellular ions. ATP-binding cassette transporters efflux compounds out of cells against a concentration gradient driven by the hydrolysis of ATP as an energy source.
Drug interactionsDrug-drug interactions occur when one drug ('perpetrator') interacts with another drug ('victim') by altering its metabolism and/or transport following coadministration. Drug-drug interactions can have serious clinical effects by decreasing the therapeutic efficacy or increasing the toxicity of a victim drug. Polypharmacy, the simultaneous use of multiple drugs in a patient for one or more conditions, increases the risk for drug interactions.Evaluation