Physiogenex SAS, Prologue Biotech, Labège, France.
Department of Cardiovascular Diseases, Atherosclerosis, Merck Research Laboratories, Rahway, NJ, USA.
Eur J Pharmacol. 2014 Oct 5;740:135-43. doi: 10.1016/j.ejphar.2014.06.022. Epub 2014 Jul 5.
Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDL- and HDL-cholesterol levels, which might be related to the potency of each drug to inhibit CETP activity. We evaluated the effects of both drugs at similar levels of CETP inhibition on macrophage-to-feces reverse cholesterol transport (RCT) in hamsters. In normolipidemic hamsters, both anacetrapib 30 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~60%. After injection of 3H-cholesteryl oleate labeled HDL, anacetrapib and dalcetrapib reduced HDL-cholesteryl esters fractional catabolic rate (FCR) by 30% and 26% (both P<0.001 vs. vehicle) respectively, but only dalcetrapib increased HDL-derived 3H-tracer fecal excretion by 30% (P<0.05 vs. vehicle). After 3H-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived 3H-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~65% and reduced HDL-cholesteryl ester FCR by 36% (both P<0.001 vs. vehicle), but only anacetrapib increased HDL-derived 3H-tracer fecal excretion significantly by 39%. After 3H-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived 3H-tracer appearance in HDL. These effects remained weaker than those observed with anacetrapib 60 mg/kg QD, which induced a maximal inhibition of CETP and stimulation of macrophage-derived 3H-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived 3H-tracer fecal excretion by 23% (P<0.05 vs. vehicle). In conclusion, anacetrapib and dalcetrapib differentially alter HDL metabolism and RCT in hamsters. A stronger inhibition of CETP may be required to promote macrophage-to-feces reverse cholesterol transport in dyslipidemic hamsters.
胆固醇酯转移蛋白 (CETP) 抑制剂达塞曲匹和阿昔单抗可不同程度地改变 LDL 和 HDL 胆固醇水平，这可能与每种药物抑制 CETP 活性的效力有关。我们评估了两种药物在相似的 CETP 抑制水平下对仓鼠巨噬细胞向粪便的胆固醇逆向转运 (RCT) 的影响。在正常脂质血症的仓鼠中，阿昔单抗 30 mg/kg QD 和达塞曲匹 200 mg/kg BID 均可抑制 CETP 活性约 60%。在注射 3H-胆甾醇油酸标记的 HDL 后，阿昔单抗和达塞曲匹分别使 HDL 胆固醇酯的分数代谢率 (FCR) 降低 30%和 26%（均 P<0.001 与载体相比），但只有达塞曲匹使 HDL 衍生的 3H 示踪剂粪便排泄增加 30%（P<0.05 与载体相比）。在 3H-胆固醇标记的巨噬细胞腹腔注射后，阿昔单抗刺激 HDL 中 3H 示踪剂的出现，但两种药物均未促进巨噬细胞衍生的 3H 示踪剂粪便排泄。在血脂异常的仓鼠中，阿昔单抗 1 mg/kg QD 和达塞曲匹 200 mg/kg BID 均可抑制 CETP 活性约 65%，并使 HDL 胆固醇酯 FCR 降低 36%（均 P<0.001 与载体相比），但只有阿昔单抗使 HDL 衍生的 3H 示踪剂粪便排泄显著增加 39%。在 3H-胆固醇标记的巨噬细胞注射后，只有阿昔单抗 1 mg/kg QD 刺激 HDL 中巨噬细胞衍生的 3H 示踪剂的出现。这些作用仍然弱于阿昔单抗 60 mg/kg QD 观察到的作用，后者诱导 CETP 的最大抑制和刺激巨噬细胞衍生的 3H 示踪剂粪便排泄。相比之下，达塞曲匹 200 mg/kg BID 使巨噬细胞衍生的 3H 示踪剂粪便排泄减少 23%（P<0.05 与载体相比）。总之，阿昔单抗和达塞曲匹可不同程度地改变仓鼠的 HDL 代谢和 RCT。在血脂异常的仓鼠中，可能需要更强的 CETP 抑制作用来促进巨噬细胞向粪便的胆固醇逆向转运。
