FATE OF 4''-EPIACETYLAMINO-4''-DEOXYAVERMECTIN B-1 IN RATS

Distribution, excretion, and metabolism of 4 ''-eplacetylamino-4 ''-de oxyavermectin B-1 (AAB(1)), a new avermectin, were determined in Sprag ue-Dawley VAF rats. The rats were dosed orally for 7 consecutive days at similar to 6 mg/kg body weight with [5-H-3]AAB(1) as a 1.2 mg/ml aq ueous suspension containing 0.5% methyl cellulose, Rats ware killed at similar to 7 hours and 1, 2, and 5 days after the last dose, The majo r route of excretion of drug residues was via feces, with less than 1% of the dose found in urine. The radioactive residue levels in tissues and blood followed the order GI > liver approximate to fat approximat e to kidney > muscle > plasma approximate to red blood cells and were comparable in male and female rats. HPLC-radiochromatographic profiles revealed that 4 ''-epiamino-4 ''-deoxyavermectin B-1a was the major m etabolite in all tissue samples and plasma samples, and was usually th e major residue at later time points, The results indicate that N-deac etylation of AAB(1) was the primary route of metabolism in rats. A dis tinct feature of the metabolism was a sex difference In the extent of the metabolism, When metabolite profiles of male and female mts killed at the same time were compared, less parent drug and more of the N-de acetylated metabolite were found in the female rats, indicating that t he drug was metabolized more extensively in female rats than in male r ats, The sex difference in the extent of metabolism was also demonstra ted in vitro.