ISSX 2010, Poster 197

ISSX 2010, Poster 197

Published:  01 September 2010

Identification of a novel carbamoyl glucuronide as a metabolism-dependent inhibitior of CYP2C8

Glucuronidation is a major route of drug biotransformation and detoxification, whereby a drug is conjugated with glucuronic acid in a reaction catalyzed by UDP glucuronosyltransferases (UGTs). However, previous reports suggest glucuronide conjugates can be inhibitors of Phase I metabolism. Of particular note is gemfibrozil glucuronide, which is oxidized by CYP2C8, causing clinically relevant irreversible inactivation of this enzyme (Ogilvie et al., 2006). In the present study, we evaluated the ability of Lu AA34893 and its carbamoyl glucuronide to inhibit in vitro the major drug metabolizing cytochrome P450 (CYP) enzymes. In NADPH-fortified human liver microsomes (HLM), Lu AA34893 was found to directly inhibit CYP2C19...