洛伐他汀与二氢吡啶类药物相互作用研究

Drug-interactions between Lovastatin and Dihydropyridin Calcium Antagonists

关键词:  洛伐他汀  二氢吡啶类药物  药物相互作用

Key words:  lovastatin  dihydropyridin calcium antagonists  drug-interaction

摘要:

目的 研究5种二氢吡啶类药物对洛伐他汀代谢的影响。方法 采用大鼠肝微粒体体外代谢模型，洛伐他汀分别与不同浓度的硝苯地平、非洛地平、拉西地平、乐卡地平和尼莫地平置于一定量的鼠肝微粒体中，于37 ℃预孵5 min后，加β-NADP/NADPH的0.1%NaHCO₃溶液启动反应，并开始记时，37 ℃下孵育20 min后，加入一定量冰乙腈沉淀蛋白并终止反应，高速离心后，上清液进HPLC分析，并分别计算硝苯地平、非洛地平、拉西地平、乐卡地平和尼莫地平对洛伐他汀代谢抑制IC50值。结果 不同结构的二氢吡啶类药物对洛伐他汀代谢的影响亦不同，其中硝苯地平的抑制作用最小(IC₅₀值为53.98 μmol·L^-1)，尼莫地平的抑制作用最大(IC50值为2.01 μmol·L^-1)，通过结构参数分析表明油水分配系数(LogP)对抑制作用影响较大成正相关，而分子量、表面积亦对抑制作用产生影响，成负相关。结论 对于患有高血压合并血脂异常的患者联合使用二氢吡啶类降压药与洛伐他汀时，产生药物相互作用的可能性较大。为避免不良反应发生，宜选用LogP值较大，而分子量、表面积较小的硝苯地平和非洛地平等。

Abstract:

OBJECTIVE To investigate the influences of five dihydropyridin calcium antagonists on the metabolism of lovastatin. METHODS The lovastatin was incubated with different concentrations of nifedipine felodipin, lacidipine, lercanidipine, and nimodipine in rat liver microsomes in vitro. The metabolic reaction was started by adding NADP/NADPH (0.9 mmol·L^-1/0.2 mmol·L^-1) after microsomal incubates being prewarmed for 5 min, continued at 37 ℃ for several periods in a shaking water bath. Then the reaction was terminated and protein was precipitated by ice acetonitrile. After the super-speed centrifugation, the supernatant was analyzed by HPLC. The inhibition parameters (IC₅₀) were calculated. RESULTS The results indicated that different dihydropyridin calcium antagonists showed different influences on the metabolism of lovastatin. The inhibition of nifedipine was mild weakest (IC₅₀=53.98 μmol·L^-1), and nimodipine was strongest(IC₅₀=2.01 μmol·L^-1). The structural analysis indicated that the LogP was positively correlated with the IC50, otherwise, the mass amu and surface area grid were negatively correlated. CONCLUSION When lovastatin and dihydropyridin calcium antagonists were administered together to treat dyslipidemia and hypertension simutanously, drug interactions with significant clinical consequences may occur. And we should choose the dihydropyridin calcium antagonist with the greater LogP and less mass amu, surface area grid, such as nifedipine and felodipin.