Metabolism of the acyl-CoA:cholesterol acyltransferase inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide in rat and monkey. Omega-/beta-oxidation pathway.
2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976) is a newly developed hypocholesterolemic agent. In pharmacokinetic studies, CI-976 was found to have a much shorter elimination half-life in monkey (0.6 hr) compared to rat (8 hr). Radioactivity analysis of biological samples from rats and monkeys administered [14C]CI-976 either iv or orally showed CI-976 to be extensively metabolized to a single major common metabolite. This metabolite was isolated and its structure determined by GC/MS, LC/MS, and NMR spectroscopy as a 6-carbon chain-shortened carboxylic acid derivative, 5,5-dimethyl-6-oxo-6-[(2,4,6-trimethoxyphenyl)amino]-hexanoic acid. A potential pathway leading to this carboxylic acid derivative may involve initial omega-oxidation followed by beta-oxidation. A potential species difference in omega-/beta-oxidative biotransformation capabilities appears to exist.
Departments of Pharmacokinetics/Drug Metabolism, Parke-Davis Pharamaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
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Woolf
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SM
Bjorge
A E
AE
Black
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A
Holmes
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T
Chang
D000284:Administration, Oral; D000813:Anilides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000813:Anilides; C069304:PD 128042; D002785:Sterol O-Acyltransferase