Identification of Novel Fatty Acid Conjugates of 4"-Deoxy-4"-epimethylaminoavermectin B1a
Abstract
The metabolism of3H/14C-labeled 4"-deoxy-4"-epimethylaminoavermectin B1a(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 B1a) and the N-demethylated derivative of 24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B1a(24-hydroxymethyl-4"-deoxy-4"-epiaminoavermectin B1a), 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 extensivein 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.
Footnotes
-
Send reprint requests to: Christopher L. Wrzesinski, Schering-Plough Research Institute, P.O. Box 32, Lafayette, NJ 07848.
-
↵1 Current address: Drug Safety & Metabolism-Animal Health, Schering-Plough Research Institute, P.O. Box 32, Lafayette, NJ 07848.
- Abbreviations used are::
- MAB1a
- 4"-deoxy-4"-epimethylaminoavermectin B1a
- MAB1b
- 4"-deoxy-4"-epimethylaminoavermectin B1b
- 24-OH-AB1a
- 24-hydroxymethyl-4"-deoxy-4"-epiaminoavermectin B1a
- 24-OH-MAB1a
- 24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B1a
- AB1
- 4"-deoxy-4"-epiaminoavermectin B1 (a mixture of B1a and B1b homologues)
- AB1a
- 4"-deoxy-4"-epiaminoavermectin B1a
- GIT
- gastrointestinal tract and contents
- APCI
- atmospheric pressure chemical ionization
- LSC
- liquid scintillation counting
- SPE
- solid-phase extraction
- EtOAc
- ethyl acetate
- TRR
- total radioactive residue(s)
- Received December 18, 1997.
- Accepted April 23, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|