Multiple mechanisms of hypocholesterolemic action of pactimibe, a novel acyl-coenzyme A:cholesterol acyltransferase inhibitor.
Novel acyl-coenzyme A:cholesterol acyltransferase inhibitor pactimibe has been evaluated in vivo; it exhibited significant serum cholesterol lowering activities in hamsters and monkeys without affecting non-high density lipoprotein cholesterol levels. The mechanism of the hypocholesterolemic action of pactimibe was examined in normocholesterolemic hamsters in this study. Results with the dual-isotope plasma ratio method indicated that pactimibe inhibits cholesterol absorption from the intestine, reduces cholesteryl ester formation in the liver, and enhances its elimination from the body. The Triton WR-1339 experiment showed that pactimibe inhibited secretion of very low density lipoprotein cholesterol from the liver. These results suggest that pactimibe is likely to have multiple mechanisms of action responsible for its effectiveness in reducing serum cholesterol.
Kitayama
Ken
K
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd. 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. kitaya@sankyo.co.jp
Koga
Teiichiro
T
Inaba
Toshimori
T
Fujioka
Tomoyuki
T
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000378:metabolism; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D007210:Indoleacetic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008647:Mesocricetus; D010743:Phospholipids / Q000097:blood; D019518:Postprandial Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D002787:Sterol Esterase / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D015243:Cholesterol, VLDL; D007210:Indoleacetic Acids; D010743:Phospholipids; D014280:Triglycerides; D002784:Cholesterol; C509302:pactimibe; D002785:Sterol O-Acyltransferase; D002787:Sterol Esterase