Metabolic Interaction between Morphine and Various Benzodiazepines

The interaction between benzodiazepines and the glucuronidation of morphine was studied in vitro and in vivo. All benzodiazepines tested (diazepam, N-desmethyldiazepam, oxazepam, lorazepam, clonazepam, nitrazepam and flunitrazepam) inhibited the glucuronidation of morphine in vitro in rat liver microsomes. Clonazepam was the most and nitrazepam the least powerful inhibitor, reducing the rate of morphine conjugation by 86% and 42% of the control, respectively, at a substrate and inhibitor concentration of 1.5 mM. Rats given a single oral dose of oxazepam (20 mg per kg body weight) one hour prior to an intraperitoneal dose of morphine (10 mg per kg body weight) had a lower morphine glucuronide/morphine concentration ratio in the 24 hour urine portion than control rats without pretreatment with oxazepam. These data indicate that oxazepam inhibits the glucuronidation of morphine in rats in vivo as well as in vitro.