Lack of Effect of Nizatidine on Drug Metabolism

Abstract

H₂-receptor antagonists are among the most widely-used drugs in the world and, since many patients receive a variety of other drugs concomitantly, it is important to investigate the interaction potential of new H₂-receptor antagonists such as nizatidine. It is well documented that cimetidine can inhibit the hepatic elimination of many drugs by binding to the cytochrome P-450 system. Therefore we investigated in vitro and in vivo the effects of nizatidine on drug metabolism. With rat liver microsomes the effects of nizatidine and four other H₂-blockers (cimetidine, oxmetidine, ranitidine, famotidine) on the activity of three marker enzymes (aryl-hydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase, 7-ethoxy-resorufin-O-deethylase) were tested. While cimetidine and oxmetidine exhibited marked and dose-dependent inhibition of all three metabolic reactions, nizatidine showed some weak inhibition only at very high concentrations. Similarly, binding to cytochrome P-450 of human liver microsomes could be seen only with cimetidine and oxmetidine, whereas nizatidine did not affect the binding spectra. In nine healthy male volunteers the pharmacokinetics of diazepam (10 mg po) was studied under the influence of nizatidine (300 mg day nocte). Nizatidine had no significant effect on the hepatic elimination of diazepam, as characterized by its elimination half-life (mean ± SD) of 35.3 ± 24.2 h (control) and 37.3 ± 18.3 h (+ nizatidine) or its total plasma clearance of 28.2 ± 12.0 ml/min (control) and 26.7 ± 10.4 ml/min (+ nizatidine). The formation of the major metabolite—desmethyldiazepam—was also unaffected by nizatidine. Likewise, the hepatic elimination of chlordiazepoxide, lorazepam, theophylline/aminophylline, warfarin, lidocaine, metoprolol and antipyrine were not impaired by nizatidine. Therefore it could be concluded that nizatidine seems to be devoid of an interaction potential on the level of hepatic drug metabolism.

Key Words:

• Cimetidine
• cytochrome P-450
• diazepam
• drug interactions
• drug metabolism
• famotidine
• H₂-receptor antagonists
• nizatidine
• oxmetidine
• ranitidine