Pharmacology and Toxicology of Nizatidine

Abstract

In well-established animal models, nizatidine is a potent, specific, and competitive orally active H₂-receptor antagonist. In rat and dog models, species in which the absorption, plasma half-life and routes of metabolism are similar to that of humans, nizatidine was three- to four-fold more active than cimetidine and was of similar potency to ranitidine. On repeated daily dosing in dogs for two weeks, no tolerance was developed to the pharmacological action. Following oral dosing to dogs, nizatidine reduced gastric acid secretion for up to 8 h suggesting that this compound could be used in humans with a once or twice daily dosage regime. Apart from its H₂-antagonist activity on the gastric mucosa, nizatidine produced few effects on the cardiovascular, respiratory, or central nervous system of animals. Nizatidine was rapidly and well-absorbed orally in mice, rats, and dogs, was widely distributed in tissues and the majority of the dose was excreted in the urine within 24 h. A similar absorption and excretion profile has been seen in humans. The plasma half-life in each of the animal species was between 1 and 2 h and no accumulation of nizatidine or its metabolites was seen in rats or dogs after daily oral administration for long periods. Similarities in the pharmacokinetic profile of nizatidine in the laboratory animals and humans supported the selection of the mouse, rat, and dog for acute and chronic toxicity studies. Nizatidine was well-tolerated in animals after both intravenous and oral administration and following single or repeated administration. Acute doses which produced significant toxic effects were very large multiples of the proposed human daily dose. Repeated oral doses in rats and dogs for up to one year did not produce significant toxic effects and no carcinogenic effects were observed in rats or mice given nizatidine in the diet for two years. Nizatidine did not cause liver enzyme induction after repeated administration to rats or dogs suggesting that this compound would not alter the hepatic drug oxidation of other drugs in humans. Nizatidine did not produce adverse effects on the fertility of rats, was not teratogenic in rats or rabbits, and did not adversely affect any part of the reproductive process of rats in a two-generation study. Based on these data, there are no contraindications for administration of this compound to humans for the treatment of ulcers at the recommended daily dosage.

Key Words:

• Animal studies
• animal toxicity
• carcinogenicity
• mutagenicity
• nizatidine
• pharmacokinetics
• safety