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Metabolism of the acyl coenzyme a cholesterol acyltransferase inhibitor 2 2 dimethyl n 2 4 6 trimethoxyphenyldodecanamide in rat and monkey omega beta oxidation pathway


, : Metabolism of the acyl coenzyme a cholesterol acyltransferase inhibitor 2 2 dimethyl n 2 4 6 trimethoxyphenyldodecanamide in rat and monkey omega beta oxidation pathway. Drug Metabolism & Disposition 19(3): 696-702

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 spectrocopy 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.

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