The Chronic Toxicity of Bemitradine, a Diuretic in Rats

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Abstract
Bemitradine, a triazolopyrimidine diuretic, was given by gavage to Sprague-Dawley rats at dosages of 0 (control), 10, 50, 220 (30/sex/dosage), and 1000 mg/kg/day (40/sex/dosage) for 52 weeks. Bemitradine-related deaths occurred only at 220 and 1000 mg/kg. There were significant decreases in body weight gain in both sexes at 50 mg/kg and higher. In contrast, there were consistent and often significant increases in feed consumption in both sexes at 220 and 1000 mg/kg. Significant bemitradine-related increases in liver weights (absolute and relative) occurred at 220 and 1000 mg/kg. Salivary gland weights (absolute and relative) were also increased at 50 mg/kg and higher. Increased salivation frequently occurred at 220 and 1000 mg/kg. Microscopically, the heart was the main target organ. Acute and chronic myocardial necrosis and inflammation were evident at 220 and 1000 mg/kg. Pericarditis also was present at the higher dosage. Myocardial necrosis often was accompanied by adrenal medullary necrosis and degeneration. Other target organs included the mesenteric arteries (hypertrophy and inflammation at 1000 mg/kg) and the liver (centrilobular hypertrophy, necrosis and nodules or adenomas at 220 and 1000 mg/kg). Hence, the threshold dosage for toxicity was between 50 and 220 mg/kg, corresponding to plasma concentrations of approximately 17 to 36 μg/mL for total bemitradine and desethylbemitradine (the main metabolite). This combination of cardiac, hepatic, arterial, adrenal, and salivary effects represents an unusual spectrum of toxicity in rats. The toxicity observed does not appear to be an extension of pharmacologic action but may be more related to chemical class.