In vitro and in vivo disposition of 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976). Identification of a novel five-carbon cleavage metabolite in rats.
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 vitro and 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 omega-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 omega-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 omega-hydroxy derivative. Separate incubation of CI-976 (omega-oxidation and beta-oxidation pathways) and M-1 (beta-oxidation only) indicated a potential gender difference in the omega-oxidation of CI-976. Both the omega-oxidation and beta-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 and L-carnitine had minor effects on the beta-oxidation of M-1, indicating beta-oxidation occurs predominately within peroxisomes.
Sinz
M W
MW
Department of Pharmacokinetics/Drug Metabolism, Parke-Davis Pharmaceutical Research, Division of Warner Lambert, Ann Arbor, MI 48105, USA.
Black
A E
AE
Bjorge
S M
SM
Holmes
A
A
Trivedi
B K
BK
Woolf
T F
TF
D000813:Anilides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D005243:Feces / Q000737:chemistry; D005260:Female; D008099:Liver / Q000201:enzymology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000813:Anilides; C069304:PD 128042; D003577:Cytochrome P-450 Enzyme System; D002785:Sterol O-Acyltransferase; D002994:Clofibrate; D010634:Phenobarbital