Identification of a Novel Five-Carbon Cleavage Metabolite in Rats
Abstract
The metabolism of CI-976, a potent inhibitor of liver and intestinal acyl coenzyme A:cholesterol acyltransferase, was investigated in isolated rat hepatocytes and Wistar rats after oral administration. The major metabolite observed both in vitroand in vivo was identified as the 6-carbon, chain-shortened 5,5-dimethyl-6-oxo-[(2,4,6-trimethoxyphenyl)amino]hexanoic acid (M-4). M-4 was determined to be formed from the ω-carboxylic acid 11,11-dimethyl-12-oxo-12-[(2,4,6-trimethoxyphenyl)amino]dodecanoic acid (M-1) via the 2- and 4-carbon, chain-shortened intermediate metabolites {9,9-dimethyl-10-oxo-10-[(2,4,6-trimethoxyphenyl)amino]decanoic acid (M-2) and 7,7-dimethyl-8-oxo-8-[(2,4,6-trimethoxyphenyl)amino]octanoic acid (M-3)}, respectively. M-1 was, in turn, determined to be derived from ω-hydroxy CI-976. A minor metabolite, identified in vitro and in vivo, was a novel 5-carbon, chain-shortened derivative, 6,6-dimethyl-7-oxo-7-[(2,4,6-trimethoxyphenyl)amino]heptanoic acid (M-5). M-5 was shown not to be formed from either M-1 or the ω-hydroxy derivative. Separate incubation of CI-976 (ω-oxidation and β-oxidation pathways) and M-1 (β-oxidation only) indicated a potential gender difference in the ω-oxidation of CI-976. Both the ω-oxidation and β-oxidation pathways were enhanced by clofibrate and phenobarbital induction, and CI-976 metabolism was completely inhibited when coincubated with SKF525A pointing to cytochrome P450-mediated metabolism, presumably CYP4A. Etomoxir andl-carnitine had minor effects on the β-oxidation of M-1, indicating β-oxidation occurs predominately within peroxisomes.
Footnotes
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Send reprint requests to: Dr. Michael W. Sinz, Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, MI 48105.
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↵1 Present address: Bayer Research, 400 Morgan Lane, West Haven, CT.
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Portions of this work were presented at the 1992 North American International Society for the Study of Xenobiotics, Bar Harbour, FL (Sinz et al., 1992).
- Abbreviations used are::
- ACAT
- acyl coenzyme A:cholesterol acyltransferase
- CI-976
- 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide
- CYP
- cytochrome P450
- M-4
- 5,5-dimethyl-6-oxo-6-[(2,4,6-trimethoxyphenyl)amino]hexanoic acid
- IS
- internal standard
- M-1
- 11,11-dimethyl-12-oxo-12-[(2,4,6-trimethoxyphenyl)amino]dodecanoic acid
- M-5
- 6,6-dimethyl-7-oxo-7-[(2,4,6-trimethoxyphenyl)amino]heptanoic acid
- BSA
- bovine serum albumin
- CMC
- carboxymethyl cellulose
- P450
- cytochrome P450
- UNK
- unknown
- M-2
- 9,9-dimethyl-10-oxo-10-[(2,4,6-trimethoxyphenyl)amino]decanoic acid
- M-3
- 7,7-dimethyl-8-oxo-8-[(2,4,6-trimethoxyphenyl)amino]octanoic acid
- Received July 18, 1996.
- Accepted October 10, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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