Human hepatic drug-metabolizing enzymes and transporters (DMETs)

Human hepatic drug-metabolizing enzymes and transporters (DMETs) constitute a comprehensive biological system responsible for the absorption, distribution, metabolism, and excretion (ADME) of both exogenous drugs and endogenous metabolites. This system is traditionally divided into Phase I enzymes, such as the Cytochrome P450 (CYP) superfamily, which catalyze oxidative reactions; Phase II enzymes, including UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), which facilitate conjugation to increase water solubility; and Phase III transporters, such as P-glycoprotein (ABCB1) and Organic Anion Transporting Polypeptides (OATPs), which manage the cellular influx and efflux of substances (Giacomini et al., 2010; Zanger & Schwab, 2013). While these proteins are not typically the primary therapeutic targets for disease modification, they are critical 'pharmacokinetic targets' that dictate the bioavailability, half-life, and systemic exposure of nearly all pharmaceutical agents. Genetic polymorphisms in DMET genes are a major source of inter-individual variability in drug response and are frequently used as biomarkers in precision medicine to avoid toxicity or therapeutic failure (FDA, 2020). Furthermore, the induction or inhibition of these enzymes and transporters by co-administered drugs is the primary mechanism underlying clinically significant drug-drug interactions (DDIs). Understanding the collective activity of this system is essential for drug development, regulatory approval, and safe clinical prescribing (Nature Reviews Drug Discovery, 2010).

Other names

ADME proteinsXenobiotic-metabolizing enzymes and transportersHepatic clearance systemPhase I, II, and III proteinsDrug processing machinery

These proteins collectively regulate the pharmacokinetics of drugs by acting as catalysts for chemical modification (enzymes) or as gatekeepers for cellular entry and exit (transporters), thereby determining the effective concentration of drugs at their intended therapeutic sites.