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Six-Month Toxicity Comparison of the Antituberculosis Drugs Aconiazide and Isoniazid in Fischer 344 Rats

Aconiazide, a hydrazone derivative of isoniazid, has been proposed for the treatment of tuberculosis. The toxicity of aconiazide was assessed by treating male and female Fischer 344 (F344) rats daily by gavage for 6 months at doses up to 400 mg/kg body wt. For comparison, the toxicity of isoniazid was determined following treatment in an identical manner at equimolar doses. Aconiazide resulted in only one death during the 6-month experiment, whereas isoniazid caused a significant increase in morbidity and mortality. Each drug induced significant dose-related decreases in body weight in both sexes, and isoniazid caused a significant decrease in liver weight in male rats. Isoniazid also induced centrilobular hepatic necrosis in male rats, a lesion not observed upon aconiazide treatment. Plasma drug levels were ≥10-fold greater in rats administered isoniazid as compared to aconiazide. The higher levels of free drug observed with isoniazid may contribute to greater toxicity of isoniazid compared to aconiazide.