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We previously reported that 3-acetyl-5-methyltetronic acid (AMT) had inhibitory effects on rat renal vitamin K1 2,3-epoxide reductase (VKOR), as well as anti-fibrotic effects on Thy-1 glomerulonephritis and cisplatin-induced renal fibrosis in rats. In the present study, we investigated the general toxicity of AMT in male Crl:CD (SD) rats following a single or 2-week oral administration. After a single oral dose up to 1,500 mg/kg, no death or bleeding tendency was observed in any animal. In the 2-week repeated toxicity study, we performed clinical observations, body weight measurements, a urinalysis, hematology, blood chemistry, gross autopsy, organ weight measurements, and histopathology. The result obtained showed significant decreases in the red blood cell count, hematocrit value, hemoglobin concentration, and urinary calcium. However, no bleeding tendency was observed, even at the highest dose of 400 mg/kg. We also confirmed that the oral bioavailability of AMT was 56.7% in a pharmacokinetic study, and the area under the blood concentration (AUC) at 400 mg/kg of the 2-week oral toxicity study in rats was markedly larger than that in renal fibrosis model rats at 30 mg/kg intravenously. We concluded that AMT does not cause systemic bleeding in rats at the dose levels which AMT showed anti-fibrotic effects.

General toxicity of a vitamin K<sub>1</sub> 2,3-epoxide reductase (VKOR) inhibitor, 3-acetyl-5-methyltetronic acid, in rats