Effect of the ACAT inhibitor CI-976 on plasma cholesterol concentrations and distribution in hamsters fed zero- and low-cholesterol diets.
The overall objective of the present study was to determine if the ACAT inhibitor CI-976 can lower plasma cholesterol in hamsters fed zero or low, "human-like" levels of cholesterol. With a purified diet containing zero dietary cholesterol, CI-976 significantly lowered VLDL cholesterol (VLDL-C), but not total plasma cholesterol (TPC). When 0.06% cholesterol was added to this diet, reductions in both VLDL and LDL cholesterol (LDL-C) lowered TPC. Efficacy was still greater with 0.2% dietary cholesterol, but not potency. Mixing CI-976 into the purified diet resulted in greater decreases in VLDL-C compared to gavage administration, but LDL-C reductions with 0.2% cholesterol were optimal with gavage. With nonpurified, chow-based diets efficacy was markedly greater with diet-admix administration, regardless of the amount of dietary cholesterol. CI-976 inhibited cholesterol absorption with chow-based diets more potently compared to nonabsorbable agents (e.g., beta-sitosterol, tigogenin cellobioside), and the lowering of LDL-C was greatest when inhibition of cholesterol absorption was maximal. We conclude that the ACAT inhibitor CI-976 is efficacious in hamster models which utilize human-like levels of dietary cholesterol. Moreover, the data suggest that the pharmacologic responses to lipophilic ACAT inhibitors in the hamster, or even other lipid-regulating drugs, are likely to depend not only on the type of basal diet but also on the mode of drug administration.
Krause
B R
BR
Department of Pharmacology, Parke-Davis Pharmaceutical Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Bousley
R F
RF
Kieft
K A
KA
Stanfield
R L
RL
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D006224:Cricetinae; D008099:Liver / Q000737:chemistry; D008297:Male; D008647:Mesocricetus; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000813:Anilides; D002791:Cholesterol, Dietary; C069304:PD 128042; D002784:Cholesterol; D002785:Sterol O-Acyltransferase