The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro–in vivo extrapolation of drug clearance and drug-drug interaction potential

Abstract

Major advances in the characterization of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) enzyme substrate and inhibitor selectivities and the development of experimental paradigms to investigate xenobiotic glucuronidation in vitro now permit the prediction of a range of drug-glucuronidation parameters in humans. In particular, the availability of substrate and inhibitor “probes” for the major hepatic drug metabolizing UGTs together with batteries of recombinant enzymes allow the reaction phenotyping of drug glucuronidation reactions. Additionally, in vitro experimental approaches and scaling strategies have been successfully applied to the quantitative prediction of in vivo clearance via glucuronidation and drug-drug interaction potential.

Keywords::

• Glucuronidation
• UDP-glucuronosyltransferase
• reaction phenotyping
• in vitro–in vivo extrapolation
• substrate probe
• inhibitor probe
• clearance prediction
• drug-drug interaction

Acknowledgment

Research support from the National Health and Medical Research Council of Australia and Pfizer Global Research (Ann Arbor) is gratefully acknowledged.