6-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 assesse d 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 tox icity of isoniazid was determined following treatment in an identical manner at equimolar doses. Aconiazide resulted in only one death durin g the 6-month experiment, whereas isoniazid caused a significant incre ase in morbidity and mortality. Each drug induced significant dose-rel ated decreases in body weight in both sexes, and isoniazid caused a si gnificant decrease in liver weight in male rats. Isoniazid also induce d centrilobular hepatic necrosis in male rats, a lesion not observed u pon aconiazide treatment. Plasma drug levels were >10-fold greater in rats administered isoniazid as compared to aconiazide. The higher leve ls of free drug observed with isoniazid may contribute to greater toxi city of isoniazid compared to aconiazide.