Fate of 4"-epiacetylamino-4"-deoxyavermectin B1 in rats

Distribution, excretion, and metabolism of 4"-epiacetylamino-4"-deoxyavermectin B1 (AAB1), a new avermectin, were determined in Sprague-Dawley VAF rats. The rats were dosed orally for 7 consecutive days at approximately 6 mg/kg body weight with [5-3H]AAB1 as a 1.2 mg/ml aqueous suspension containing 0.5% methyl cellulose. Rats were killed at approximately 7 hours and 1, 2, and 5 days after the last dose. The major 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 approximately equal to fat approximately equal to kidney > muscle > plasma approximately equal to red blood cells and were comparable in male and female rats. HPLC-radiochromatographic profiles revealed that 4"-epiamino-4"-deoxyavermectin B1a was the major metabolite in all tissue samples and plasma samples, and was usually the major residue at later time points. The results indicate that N-deacetylation of AAB1 was the primary route of metabolism in rats. A distinct feature of the metabolism was a sex difference in the extent of metabolism. When metabolite profiles of male and female rats killed at the same time were compared, less parent drug and more of the N-deacetylated metabolite were found in the female rats, indicating that the drug was metabolized more extensively in female rats than in male rats. The sex difference in the extent of metabolism was also demonstrated in vitro.