UDP-Glucuronosyl transferase mediated drug-drug interactions: An Industry perspective on recommended in vitro studies

Uridine 5'-diphospho-glucuronosyltransferases (UGT) are the best known and most well characterized sugar conjugation biotransformation enzymes. Their main function is to catalyze conjugation of glucuronic acid (sugar) to an exposed (or created) hydroxyl, amine or other nucleophilic functional group on a substrate, known as an aglycone. Since these enzymes are subject to inhibition and induction, there is considerable interest in characterizing their role in mediating drug-drug interactions. Glucuronidation reactions are readily recreated in vitro, although most researchers agree rates of catalysis continue to be underestimated compared to those in vivo, thus hampering the prediction of human systemic clearance. Similarly, the magnitude of UGT induction observed in vitro appears to be smaller than those reported in clinical trials. Despite these shortcomings, drug candidates and marketed drugs rarely encounter clinically relevant pharmacokinetic changes attributable to UGT enzyme inhibition or induction. This is likely due to a combination of enzyme properties (high capacity/low affinity, high promiscuity, and minimal inducibility). By contrast, genetic polymorphisms resulting in poor metabolizer or null phenotypes have been demonstrated to have considerable impact on drug disposition, underscoring the need to characterize the fraction of drug metabolized by polymorphic enzymes, especially when glucuronidation is a major clearance mechanism. Recent developments in identifying specific chemical inhibitors and substrate probes, as well as enzyme induction test systems, are helping to further investigate UGT function and role in drug disposition. The aim of this review is to provide an overview of these recent advances and an industry perspective on in vitro testing of UGT-mediated drug-drug interaction potential.