Vol. 26, Issue 8, 786-794, August 1998

Metabolism of ³H/¹⁴C-Labeled 4"-Deoxy-4"-epimethylaminoavermectin B_1a Benzoate in Chickens
Identification of Novel Fatty Acid Conjugates of 4"-Deoxy-4"-epimethylaminoavermectin B_1a

Christopher L. Wrzesinski,¹ Mohammad Mushtaq,¹ Terry Faidley, Nelson Johnson, Byron Arison, and Louis S. Crouch¹

Pesticide Metabolism and Environmental Safety Group (C.L.W., M.M., L.S.C.), Branchburg Farms (T.F.), Agricultural Research and Development (N.J.), and Department of Drug Metabolism-Rahway (B.A.), Merck Research Laboratories

The metabolism of ³H/¹⁴C-labeled 4"-deoxy-4"-epimethylaminoavermectin B_1a (MAB1a) benzoate, the major homologue (90%) of the avermectin insecticide emamectin benzoate, was studied in laying chickens. Ten Leghorn hens (Gallus domesticus) were orally dosed once daily for 7 days (1 mg/kg of body weight/day). Eggs and excreta were collected daily, and eggs were subsequently separated into whites and yolks. Chickens were euthanized within 20 hr after the last dose, and liver, kidney, heart, muscle, fat, ovaries, gizzard, gastrointestinal tract and contents, and carcass were collected. Approximately 70 and 6% of the total administered dose were recovered in the excreta plus gastrointestinal tract and contents and in the tissues plus eggs, respectively. Two novel metabolites, i.e. the 24-hydroxymethyl derivative of the parent compound (24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B_1a) and the N-demethylated derivative of 24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B_1a (24-hydroxymethyl-4"-deoxy-4"-epiaminoavermectin B_1a), were identified. In addition, eight fatty acid conjugates of each of these two metabolites, comprising 8-75% of total radioactive residues in tissues and eggs, were isolated and identified. Although this represents some of the most extensive in vivo fatty acid conjugation to a xenobiotic reported to date, potential human exposure to MAB1a residues from consumption of chicken would be extremely low, because the dosage level in this study was ~1000-fold greater than the MAB1a residue levels seen in crops and because the majority of the applied dose was recovered in the excreta. Based on these findings, the avian biotransformation of MAB1a differs substantially from the mammalian biotransformation.