The In Vitro Characterization of Inhibitory Drug-Drug Interactions Involving UDP-Glucuronosyltransferase

Inhibition of UDP-glucuronosyltransferase (UGT) activity gives rise to both drug-drug (DDIs) and drug-endobiotic interactions in vivo. Furthermore, several glucuronides have been shown to reduce the metabolic clearances of cytochrome P4502C8 substrates. Experimental paradigms, based on the use of human liver microsomes (HLM), hepatocytes, and recombinant UGTs as the enzyme sources, are now available for the investigation of drug glucuronidation in vitro including the prediction and characterization of DDIs. The reaction phenotyping of drug glucuronidation is becoming increasingly feasible with the availability of 'batteries' of recombinant enzymes along with substrate and inhibitor probes for the major hepatic drug metabolizing UGTs. However, the occurrence of homo- and heterotropic activation potentially complicates screening for DDIs in vitro. Recent advances in knowledge of factors that influence UGT activity in vitro have also led to the development of experimental approaches that accurately predict the magnitude of known DDIs involving glucuronidated drugs, but further work in this area is required to demonstrate the generalizability of these models.