The Preclinical Toxicity of Dazoxiben: A Specific Inhibitor of Thromboxane A2 Synthetase
The recent discovery of highly selective inhibitors of thromboxane synthetase has opened exciting new therapeutic possibilities in cardiovascular disease, ranging from peripheral vascular disorders, angina and ischaemic heart disease to atherosclerosis. One such agent, dazoxiben (4–2-(1H-imidazol-l-yl)ethoxy benzoic acid) has been shown to be orally active in man. Clinical studies are currently in progress, the therapeutic dose being of the order of 2–3 mg/kg, three times per day (Tyler 1983).
The first animal toxicity studies with this compound are reported here. For reference, a long-lasting orally effective dose of dazoxiben in the dog is ca. 3 mg/kg. Beagle dogs and Sprague-Dawley rats which received dazoxiben orally for 6 months showed no evidence of toxicity at daily dose levels of 300 and 100 mg/kg respectively. Only in rats which received the highest dose level (400 mg/kg) were drug-related effects seen. Some changes in clinical chemistry and haematological parameters were seen and, in the females, some microscopically detected kidney changes. Reproductive studies in rats and rabbits revealed no adverse effects of dazoxiben on male or female fertility, embryogenesis, parturition or post-natal development up to the highest dose used, 400 mg/kg/day. The low toxicity found in these oral studies is not due to poor oral absorption of drug high and dose-related concentrations of drug were found in the plasma.
The generally favorable toxicological profile of dazoxiben, especially the absent or negligible effects on the g.i. tract, the kidney, coagulation and parturition (all prostaglandin sensitive organs or functions) augurs well for the safety of dazoxiben in clinical use.
Key wordsDazoxiben Thromboxane A2 synthetase Rats Dogs Preclinical toxicity
- Tyler HM (1983) Dazoxiben: A pharmacological tool or clinical candidate? Br J Clin Pharmacol 15: 13–16 and references cited thereinGoogle Scholar