Differential inhibition by diazepam and nitrazepam of UDP-glucuronyltransferase activities in rats.

To assess the role of the N-alkyl group in the interaction of N-alkylated compounds on UDP-glucuronyltransferases, the effect of diazepam and nitrazepam, an N-desmethyl derivative of the diazepam class was studied on morphine, p-nitrophenol and testosterone glucuronidation in rats. Diazepam competitively inhibited the UDP-glucuroyltransferase activity for morphine in hepatic microsomes. The k value for morphine was 0.3 mM and the Ki for diazepam was about 0.23 mM. Also, diazepam administration to male rats reduced the glucuronyltransferase activity for morphine in rat hepatic microsomes in a dose effect relationship. Nitrazepam had no significant effect on morphine UDP-glucuronyltransferase activity in vitro or in in vivo experiments. Neither diazepam nor nitrazepam produced any effect on p-nitrophenol or testosterone glucuronidation in liver microsomal preparations. Single or repeated doses of these benzodiazepines did not change cytochrome P-450, RNA or protein contents of hepatic microsomes. It is suggested that morphine glucuronyltransferase contains an active site for binding of the N-methyl group present in the substrate. Such a binding site would be absent or in effective in p-nitrophenol and testosterone glucuronyltransferases. The reported inhibition of morphine metabolism by diazepam may account for an enhancement of morphine pharmacological effects.