Inhibition of ciramadol glucuronidation by benzodiazepines.

Studies on the inhibition of ciramadol glucuronidation by benzodiazepines were performed in vitro and in vivo. Ciramadol glucuronidation was slower (Vmax, 1.56 vs. 5.40 nmol/min/mg of microsomal protein) in human than in dog liver microsomes. Inhibition constants (Ki) for lorazepam and oxazepam were 3 to 4 times higher than that calculated for diazepam. Rates of morphine glucuronidation in human liver microsomes were assessed for comparative purposes and agreed with literature values. Each benzodiazepine appeared to be a competitive inhibitor of ciramadol and morphine UDP-glucuronyltransferase activity. The in vivo disposition of ciramadol was unchanged in dogs pretreated with lorazepam. After diazepam treatment no change in the Vdss of ciramadol occurred, but plasma clearance was significantly reduced, resulting in a prolongation of t1/2. Diazepam caused a significant reduction in the oral clearance of ciramadol, whereas no change occurred in systemic availability. Thus, diazepam may have had a secondary effect on hepatic blood flow (QH) and produced offsetting alterations in both intrinsic clearance (Cl int) and QH. A decrease in the area under the plasma concentration time curves of ciramadol aryl O-glucuronide following iv treatment with diazepam coupled with the in vitro data indicate that the mechanism for the decrease in the clearance of ciramadol is inhibition of its glucuronidation by diazepam. Since glucuronidation plays a major role in the elimination of ciramadol in man and dog, these experiments suggest that the disposition of ciramadol in man would not be affected by coadministration of lorazepam, whereas the potential for a diazepam/ciramadol drug interaction in humans exists.