TY - JOUR T1 - <em>In Vitro</em> and <em>In Vivo</em> Disposition of 2,2-Dimethyl-<em>N</em>-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976) JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 123 LP - 130 VL - 25 IS - 1 AU - Michael W. Sinz AU - Ann E. Black AU - Susan M. Bjorge AU - Ann Holmes AU - Bharat K. Trivedi AU - Thomas F. Woolf Y1 - 1997/01/01 UR - http://dmd.aspetjournals.org/content/25/1/123.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -