Phenotyping UDP-Glucuronosyltransferases (UGTs) Involved in Human Drug Metabolism: An Update

Glucuronidation, catalyzed by the UDP-glucuronosyltransferases (UGT), is a major drug clearance mechanism in humans and other mammalian species. UGT reaction phenotyping involves determining which of the 19 known human UGTs are primarily responsible for glucuronidation of a particular drug. This approach is commonly used during the drug development process for drugs that are clearly primarily by glucuronidation, thereby enabling rational predictions of potential drug interactions and pharmacogenomic variation. An integrated approach to phenotyping is described using recombinant expressed UGTs, comparative enzyme kinetic analysis, correlations with UGT selective probe activities, relative activity factor normalization, and chemical inhibition. Updated protocols are provided that overcome several newly discovered model limitations, including endogenous fatty acid inhibition of UGT2B7 and UGT1A9 activities.