IN-VITRO AND IN-VIVO DISPOSITION OF ,2-DIMETHYL-N-(2,4,6-TRIMETHOXYPHENYL)DIDECANAMIDE (CL-976) - IDENTIFICATION OF A NOVEL 5-CARBON CLEAVAGE METABOLITE IN RATS

The metabolism of Cl-976, a potent inhibitor of liver and intestinal a cyl coenzyme A:cholesterol acyltransferase, was investigated in isolat ed rat hepatocytes and Wistar rats after oral administration. The majo r metabolite observed both in vitro and in vivo was identified as the 6-carbon, chain-shortened thyl-6-oxo-[(2,4,6-trimethoxyphenyl)amino]he xanoic acid (M-4), M-4 was determined to be formed from the omega-carb oxylic acid 2-oxo-12-[(2,4,6-trimethoxyphenyl)amino]dodecanoic acid (M -1) via the 2- and 4-carbon, chain-shortened intermediate metabolites -10-oxo-10-[(2,4,6-trimethoxyphenyl)amino]decanoic acid; (M-2) and yl- 8-oxo-8-[(2,4,6-trimethoxyphenyl)amino]decanoic acid (M-3) h respectiv ely. M-1 was, in turn, determined to be derived from omega-hydroxy Cl- 976, A minor metabolite, identified in vitro and in vivo, was a novel 5-carbon, chain-shortened derivative, l-7-oxo-7-[(2,4,6-trimethoxyphen yl)amino]heptanoic acid (M-5). M-5 was shown not to be formed from eit her M-1 or the omega-hydroxy derivative. Separate incubation of Cl-976 (omega-oxidation and beta-oxidation pathways) and M-1 (beta-oxidation only) indicated a potential gender difference in the omega-oxidation of Cl-976, Both the omega-oxidation and beta-oxidation pathways were e nhanced by clofibrate and phenobarbital induction, and Cl-976 metaboli sm was completely inhibited when coincubated with SKF525A pointing to cytochrome P450-mediated metabolism, presumably CYP4A, Etomoxir and L- carnitine had minor effects on the beta-oxidation of M-1, indicating b eta-oxidation occurs predominately within peroxisomes.