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Published on: March 25, 2020
Effect of the ACAT inhibitor CI-976 on plasma cholesterol concentrations and distribution in hamsters fed zero- and
B R Krause1, R F Bousley, K A Kieft
1Department of Pharmacology, Parke-Davis Pharmaceutical Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Insights
The ACAT inhibitor CI-976 effectively lowers cholesterol in hamsters on human-like diets. Drug administration method and diet type significantly impact cholesterol reduction, particularly LDL-C levels.
Area of Science:
- Pharmacology
- Biochemistry
- Cardiovascular Research
Background:
- Cholesterol metabolism is crucial for cardiovascular health.
- ACAT inhibitors represent a potential therapeutic strategy for hypercholesterolemia.
- Understanding drug efficacy requires considering dietary and administration variables.
Purpose of the Study:
- To evaluate the efficacy of ACAT inhibitor CI-976 in lowering plasma cholesterol in hamsters.
- To investigate the impact of varying dietary cholesterol levels on CI-976's effectiveness.
- To determine the influence of administration route (diet admix vs. gavage) on CI-976's lipid-lowering effects.
Main Methods:
- Hamsters were fed purified diets with zero or low (0.06%, 0.2%) cholesterol.
- CI-976 was administered via diet admix or gavage.
- Plasma lipid profiles, including VLDL-C, LDL-C, and TPC, were analyzed.
- Cholesterol absorption was assessed using nonabsorbable agents.
Main Results:
- CI-976 significantly reduced VLDL-C in hamsters on zero-cholesterol diets.
- Reductions in VLDL-C and LDL-C led to lower TPC with 0.06% dietary cholesterol.
- Diet admixing enhanced VLDL-C reduction, while gavage optimized LDL-C reduction at 0.2% cholesterol.
- On chow-based diets, CI-976 potently inhibited cholesterol absorption, leading to maximal LDL-C lowering.
Conclusions:
- ACAT inhibitor CI-976 demonstrates efficacy in hamster models with human-like dietary cholesterol levels.
- The effectiveness of CI-976 and potentially other lipid-regulating drugs is influenced by diet composition and administration method.
- Optimal therapeutic outcomes may depend on tailoring administration strategies to specific dietary contexts.
Abstract:
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.
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