Effect of selective phase II enzyme inducers on glucuronidation of benoxaprofen in rats

Abstract

The induction of benoxaprofen (BNX) glucuronidation in rats by intragastric administration of three nitrogen heterocycles (quinoline, 2,2'-dipyridyl, or 1,7-phenanthroline at 75 mg/kg daily for 3 days) has been investigated. BNX was administered i.v. at a dose of 20 mg/kg to bile-cannulated rats that had been induced. Blood and bile were collected over 8 h. Liver tissues were also collected at the end of the 8-h study and used to examine conjugation activity of BNX by UDP-glucuronosyl transferases and cytochrome P-450 enzyme activities in vitro. Two methods were used to characterize the true metabolic formation rates of the labile benoxaprofen glucuronide conjugate in vitro, which gave comparable mean values for K(M) and V(max). There appeared to be a trend of increase of the V(max) of BNX glucuronidation in rat liver microsomes by all three nitrogen heterocycles; however, the induction was only significant with 1,7-phenanthroline. K(M) was not noticeably altered by any of the three inducers. No change of measured hepatic microsomal cytochrome P-450 activities in the rat was found. BNX glucuronidation in rats in vivo was increased by all three nitrogen heterocycles with 1,7-phenanthroline more effective than quinoline and 2,2'-dipyridyl. The use of nitrogen heterocycles provides a means to modulate exposure to labile, reactive acyl glucuronides in vivo without apparent changes in oxidative metabolism.