Biodisposition studies with the acyl-coenzyme A: cholesterol acyltransferase inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, CI-976.
2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, CI-976, is a newly developed fatty acid anilide being evaluated as a plasma lipid regulator and antiatherosclerotic agent. Disposition studies with CI-976 were conducted in rats and monkeys. In rats, CI-976 (suspension, 50 mg/kg) was approximately 30% bioavailable, with 46% of the administered radioactivity recovered in urine suggesting presystemic metabolism. The intravenous elimination half-life of CI-976 in rats was approximately 8 hr. Radioactivity derived from [14C]CI-976 was almost completely recovered in rats after either oral or intravenous administration. In bile duct-cannulated rats receiving either an oral or intravenous dose, biliary excretion was the major route of drug-derived radioactivity elimination. There was no evidence for unchanged drug in urine or bile. In monkeys, 13% urinary recovery and 5% bioavailability was achieved after a single 50 mg/kg suspension dose. Similar values were obtained following a 250 mg/kg dose. Monkeys displayed a CI-976 elimination half-life of 0.6 hr after a 2 mg/kg intravenous dose. No unchanged drug was excreted in urine. In summary, CI-976 exhibits moderate absorption and bioavailability in the rat, but lower absorption and bioavailability in monkey. A special difference in CI-976 elimination half-life was observed consistent with in vitro metabolism results.
Woolf
T F
TF
Department of Pharmacokinetics/Drug Metabolism, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Black
A
A
Shum
Y Y
YY
McNally
W
W
Lee
H
H
Chang
T
T
D000284:Administration, Oral; D000813:Anilides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D001682:Biological Availability; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D000813:Anilides; D002250:Carbon Radioisotopes; C069304:PD 128042; D002785:Sterol O-Acyltransferase