Influence of cimetidine on bupivacaine disposition in rat and monkey.

Recent reports have appeared describing a cimetidine-induced alteration in either the input or disposition function for many drugs. The total clearance component of the disposition function is the primary perturbation. In the present investigation, the influence of cimetidine on bupivacaine disposition was studied, using in vitro and in vivo models. Since the extraction ratio for bupivacaine is low, total clearance follows the capacity-limited theory. Hence, the influence of cimetidine on the intrinsic clearance of bupivacaine was assessed using microsome and hepatocyte models. Results for both systems are in excellent agreement and indicate a noncompetitive inhibition. Additionally, the influence of cimetidine on the protein-binding profile of bupivacaine was determined. In the presence of cimetidine, the these findings was assessed in vivo in rhesus monkeys. co-administration of cimetidine resulted in an increase in the volume of distribution at steady state and no change in the total clearance of bupivacaine.