In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises

Biochem Pharmacol. 2006 May 28;71(11):1531-9. doi: 10.1016/j.bcp.2005.12.019. Epub 2006 Feb 7.

Abstract

Enzymes of the UDP-glucuronosyltransferase (UGT) superfamily are responsible for the metabolism of many drugs, environmental chemicals and endogenous compounds. Identification of the UGT(s) involved in the metabolism of a given compound ('reaction phenotyping') currently relies on multiple confirmatory approaches, which may be confounded by the dependence of UGT activity on enzyme source, incubation conditions, and the occurrence of atypical glucuronidation kinetics. However, the increasing availability of substrate and inhibitor 'probes' for the individual UGTs provides the prospect for reliable phenotyping of glucuronidation reactions using human liver microsomes or hepatocytes, thereby providing data directly relevant to drug metabolism in humans. While the feasibility of computational prediction of UGT substrate selectivity has been demonstrated, the development of easily interpretable and generalisable models requires further improvement in the datasets available for analysis. Quantitative prediction of the hepatic clearance of glucuronidated drugs and the magnitude of inhibitory interactions based on in vitro kinetic data is more problematic. Intrinsic clearance (CL(int)) values generated using human liver microsomes under-predict in vivo hepatic clearance, typically by an order of magnitude. In vivo clearances of glucuronidated drugs are also generally under-predicted by CL(int) values from human hepatocytes, but to a lesser extent than observed with the microsomal model. While it is anticipated that systematic analysis of the potential causes of under-prediction may provide more reliable in vitro-in vivo scaling strategies, mechanistic interpretation of in vitro-in vivo correlation more broadly awaits further advances in our understanding of the structural and cellular determinants of UGT activity.

Publication types

  • Review

MeSH terms

  • Glucuronides / metabolism*
  • Glucuronosyltransferase / metabolism*
  • Hepatocytes / metabolism
  • Humans
  • Metabolic Clearance Rate
  • Microsomes, Liver / metabolism
  • Pharmaceutical Preparations / metabolism*
  • Phenotype
  • Substrate Specificity

Substances

  • Glucuronides
  • Pharmaceutical Preparations
  • Glucuronosyltransferase