Nizatidine, a new histamine H₂-receptor antagonist, and hepatic oxidative drug metabolism in the rat: A comparison with structurally related compounds

The effects of nizatidine (a new H₂-receptor antagonist) and of related compounds were studies on oxidative drug metabolism in the rat both in vivo and in vitro. Nizatidine is a structural analog of the H₂-receptor antagonists ICI 125,211 (Tiotidine) and ranitidine (Zantac). Nizatidine (120 mg/kg, ip) had no effect on the [¹⁴C]aminopyrine (ABT) or [¹⁴C]caffeine breath (CBT) tests, nor on the clearance from plasma of aminopyrine despite high tissue and plasma concentrations of nizatidine. Binding of nizatidine (1 mm) to rat hepatic microsomal P-450 determined by spectral analysis was not observed. In vitro aminopyrine demethylation was inhibited by nizatidine only at high concentrations (K_i = 92 mm). Cimetidine, ICI 125,211, and imidazole bind avidly to rat hepatic microsomal cytochrome P-450 and are potent inhibitors of aminopyrine demethylation in vitro. Imidazole inhibited the aminopyrine breath test, while imidazole, ranitidine, and ICI 125,211 inhibited the caffeine breath in vivo. These data indicate that nizatidine has no acute inhibitory effect on hepatic oxidative drug metabolism in the rat, both in vitro and in vivo. The composite structural-activity data suggest that inhibition of in vivo oxidative drug metabolism by H₂-antagonists may not depend primarily on either the imidazole ring side chain or the thiazole ring per se. Furthermore, the in vivo inhibition may not correlate with in vitro data.