Chapter 14
Ivermectin and Abamectin Metabolism Differences and Similarities Bruce A. Halley, Narayana I. Narasimhan, Kalpana Venkataraman, Rae Taub, Marilyn L. G. Erwin, Nicholas W. Andrew, and Peter G. Wislocki
Downloaded by UNIV LAVAL on May 13, 2016 | http://pubs.acs.org Publication Date: August 24, 1992 | doi: 10.1021/bk-1992-0503.ch014
Merck Sharp & Dohme Research Laboratories, Merck & Company, Inc., P.O. Box 2000, Rahway, NJ 07065
The metabolic fates of ivermectin (IVM) and abamectin (avermectin B , AVM) were previously studied in our laboratory. The major metabolites of the components of IVM, H B and H B , in cattle, sheep and rats were the 24-hydroxymethyl (24-OHMe) compounds, while the major metabolites in swine were the 3"-O -desmethyl (3"-ODMe) compounds. For IVM, there was no identification of 24-OHMe compounds in the swine, no identification of 3"-ODMe compounds in cattle or sheep and evidence for only trace amounts of 3"-ODMe compounds in the rat. For AVM (or its major component B ), however, both metabolic pathways were evident in all species tested. Hydroxylation of the 24-methyl group was the major metabolic pathway in cattle and goats, while 3"-O-desmethylation was identified as a minor pathway. In rats, 3"-ODMe-B was the major metabolite and 24OHMe-B was a minor one. Thus, it appeared there were inter -and intra-species differences in the metabolism of IVM and AVM. Recently, we re-examined the metabolism of IVM and AVM in cattle, swine and rats. We identified 3"-ODMe-H B in the livers of steers dosed orally with [ H]H B and following incubations of [ H]H B with steer liver microsomes. We also identified 24OHMe metabolites in the livers of swine fed [ H]IVM for seven days. In in vitro studies of [ H]H B and [ H]B with microsomes from livers of untreated steers, swine and rats, similar metabolic profiles were obtained. Also, 3"-ODMe-H B and 3"-ODMe-B were identified as in vitro metabolites of IVM and AVM, respectively, in rats. Thus, the rat is a good laboratory animal toxicity model for both cattle and swine. The results of these studies indicate that IVM and AVM are metabolized qualitatively similarly by cattle, swine and rat and that the metabolic profiles for each compound are qualitatively similar among the species. 1
2
1a
2
1b
1a
1a
1a
2
1a
3
2
1a
3
2
1a
3
3
3
2
1a
1a
2
1a
0097-6156/92/0503-0203$06.00/0 © 1992 American Chemical Society
Hutson et al.; Xenobiotics and Food-Producing Animals ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
1a
204
XENOBIOTICS AND FOOD-PRODUCING
ANIMALS
The avermectins are a family of fermentation products possessing a 16-member cyclic lactone, a spiroketal moiety and a disaccharide unit. Avermectin B i is a mixture of two components which possess a double bond at position 22,23 and differ by a methylene group in the side-chain substituents at position 25. The mixture containing >80% avermectin B i (Bi ) and
