Some H2-receptor antagonists can interact with the biotransformation of other drugs. This is due to their binding to cytochrome P-450. We tested the in vitro effects of 5 different H2-receptor antagonists cimetidine (C), oxmetidine (O), ranitidine (R), famotidine (F) and nizatidine (N) on arylhydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase and 7-ethoxy-resorufin-O-deethylase activity using liver microsomes from man as well as from untreated, phenobarbital and 3-methylcholanthrene treated 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 volunteers. In vitro O was found to be the most effective inhibitor of the enzyme activities studied. C showed a clear inhibitory effect only with rat liver microsomes whereas the remaining drugs were more than 10 times less potent. The binding affinities of these antagonists showed a similar tendency: the Ks-values for O, C and R were 0.2, 0.9 and 5.1 mM, respectively; for F and N no binding up to 4 mM could be observed. However, in man, only C inhibited the hepatic elimination of diazepam by about 45% while R, O, N and F did not affect the pharmacokinetics of diazepam. Thus, it could be concluded from our studies that one cannot extrapolate in vitro data of the inhibitory potency of H2-receptor antagonists in every case to human in vivo drug metabolism.