Potency of select statin drugs in a new mouse model of hyperlipidemia and atherosclerosis

Poloxamer-407 (P-407) is a nonionic surfactant that induces atheroma format ion in the aortas of C57BL/6 mice with long-term (14 weeks) administration. The objectives of the present study were to determine the mechanism(s) res ponsible for the induction of hypercholesterolemia as well as to determine whether this animal model may be of potential use in rank ordering the effi cacy (lipid lowering) of various statin drugs. The effect of long-term (16 weeks) administration of P-407 on the catalytic activities of rate-limiting enzymes of cholesterol biosynthesis [HMG-CoA reductase (HMGR)] and catabol ism [microsomal cholesterol 7 alpha -hydroxylase (C7 alphaH) and mitochondr ial sterol 27 hydroxylase (S27H)] was assessed in C57BL/6 mice. Effects of P-407 on these enzymes were compared in mice fed an atheroma-inducing diet (high-cholesterol, supplemented with cholic acid) and animals maintained on a basal diet and injected with saline (controls) after 16 weeks. The mean value for the activities of C7 alphaH in P-407-injected mice was 24.3 +/- 3 .8 pmol min(-1) mg(-1) and was significantly (P < 0.05) less than the mean value determined for sham-injected control animals (37.0 +/- 14.3 pmol min( -1) mg(-1)). In contrast, the mean values for the catalytic activities of S 27H and HMGR did not change with P-407 administration. Neither C7 alphaH no r S27H activity in mice fed the high-cholesterol diet differed from values for control animals, whereas the mean HMGR activity was drastically reduced (- 94%, P < 0.05). The hypercholesterolemic effect of P-407 is not due to altered cholesterol biosynthesis, but is mediated by reduced cholesterol ca tabolism due to decreased activity of the rate limiting enzyme (C7 alphaH) in the classic bile acid synthetic pathway. Plasma triglyceride lowering re sulting from the oral administration of equal doses of various statin drugs appeared, in general, to be positively correlated with their relative aque ous solubility and paralleled the efficacy of these agents to lower low-den sity-lipoprotein-associated cholesterol (LDL-C) in humans. The plasma trigl yceride lowering effect of the five statin drugs tested produced the follow ing rank order; pravastatin sodium (- 44%) > atorvastatin calcium (- 36%) > simvastatin (- 33%) > lovastatin (- 25%) > fluvastatin sodium (- 19%). Whi le reductions in plasma total cholesterol following administration of the s tatin drugs was not as profound as that observed with triglycerides, the re lative rank order or trend was preserved. The percent reduction in plasma t riglycerides in the present model appears to be a useful parameter with whi ch to predict the relative reduction in plasma LDL-C expected for these age nts in humans. (C) 2001 Elsevier Science B.V. All rights reserved.