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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The inhibitory effects of roxatidine acetate hydrochloride (ROX), a new H_2-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 6β-, 7α- and 16α-hydroxylase, aminopyrine N-demethylase and aniline hydroxylase activities in mouse hepatic microsomes with inhibition constants (K_i) of 0.2-3.49 mM. ROX exhibited much weaker inhibitory effects on each enzyme activity with 12 to 100-fold higher values of K_i than those of CIM. CIM gave type II difference spectra with dissociation constants (K_s) of 10.4 and 111 μM while ROX gave reverse type I difference spectra with K_s of 55.6 μM. The ratio of 6β-hydroxycortisol (6β-OHF) to 17-hydroxy corticosteroids (17-OHCS) in urine, used as an indicator of oxidative drugmetabolizing 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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