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 forK_M and V_max. There appeared to be a trend of increase of theV_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.