Comparative effects of H 2-receptor antagonists on drug metabolism in vitro and in vivo

Abstract

Some H 2-receptor antagonists can interact with the biotransformation of other drugs. This is due to their selective binding to the various forms of cytochrome P-450. We tested the in vitro effects (IC 50) of 5 different H 2-receptor antagonists (Cimetidine (C), Oxmetidine (O), Ranitidine (R), Famotidine (F) and Nizatidine (N)) on aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin- O-deethylase (ECDE) and 7-ethoxyresorufin- O-deethylase (ERDE) activities using microsomes from rats. In addition, their binding to human microsomal cytochrome P-450 was evaluated. The in vivo effects of these antagonists were investigated on the hepatic elimination of diazepam in healthy human volunteers. O was found to be the most effective inhibitor (IC 50=0.1 to 0.3mM) of the enzyme activities studied. C also showed a clear inhibitory effect (IC 50=0.4 to 0.7 mM) whereas the remaining drugs were more than 10 times less potent. Likewise, when diazepam was used as a substrate, microsomal conversion to desmethyldiazepam and temazepam was inhibited by oxmetidine (IC 50=0.02 mM). The binding effects of these antagonists showed the same tendency. However, only C had a clear inhibitory effect on the elimination of diazepam while R,O,N and F did not affect the pharmacokinetics of diazepam. Thus, it could be concluded from our structure/activity relationship studies that one cannot extrapolate, in every case, in vitro data to the inhibitory potency of H 2-receptor antagonists on human drug metabolism.