A comparison of the inhibitory effects of roxatidine acetate hydrochloride and cimetidine on cytochrome P-450-mediated drug-metabolism in mouse hepatic microsomes and in man in vivo.

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Abstract
The inhibitory effect of roxatidine acetate hydrochloride (ROX), a new H2-receptor antagonist, on the oxidative drug-metabolizing enzyme system in mouse hepatic microsomes and in man in vivo were compared with those of cimetidine (CIM). CIM markedly inhibited testosterone 6.beta.-, 7.alpha.- and 16.alpha.-hydroxylase, aminopyrine N-demethylase and aniline hydroxylase activities in mouse hepatic microsomes with inhibition constants (Ki) of 0.2-3.49 mM. ROX exhibited much weaker inhibitory effects on each enzyme activity with 12 to 100-fold higher values of Ki than those of CIM. CIM gave type II difference spectra with dissociation constants (Ks) of 10.4 and 111 .mu.M while ROX gave reverse type I difference spectra with Ks of 55.6 .mu.M. The ratio of 6.beta.-hydroxycortisol (6.beta.-OHF) to 17-hydroxycorticosteroids (17-OHCS) in urine, used as an indicator of oxidative drug-metabolizing capacity in man, was decreased by 25-35% of the original level on 1-3 d after oral treatment with 800 mg/d of CIM. The ratio was not significantly changed during oral treatment with 150 mg/d of ROX. These results indicate that ROX exhibits a lower affinity for cytochrome P-450 and a lower inhibitory potency on the drug-metabolizing enzymes in hepatic microsomes than does CIM.

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