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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53.98μmol·L-1),尼莫地平的抑制作用最大(IC50值为2.01μmol·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。
Objective To study the effects of five dihydropyridines on the metabolism of lovastatin. Methods Rat liver microsomes in vitro metabolism model was used. Lovastatin was placed in a certain amount of rat liver microsomes with different concentrations of nifedipine, felodipine, lacidipine, lercanidipine and nimodipine, respectively. After preincubation at 37 ° C for 5 min, the reaction was started with β-NADP / NADPH in 0.1% NaHCO 3 solution and the recording was started. After incubating at 37 ° C for 20 min, a certain amount of ice-acetonitrile was added to precipitate the protein and the reaction was stopped. The supernatant was analyzed by HPLC, and the IC50 values of inhibition of lovastatin metabolism by nifedipine, felodipine, lacidipine, lercanidipine and nimodipine were respectively calculated. Results Dihydropyridines with different structures had different effects on lovastatin metabolism, of which nifedipine had the least inhibitory effect (IC50 value was 53.98μmol·L-1) and nimodipine had the greatest inhibitory effect (IC50 was 2.01μmol·L-1). The analysis of structural parameters showed that LogP had a positive effect on the inhibitory effect, while the molecular weight and surface area also had a negative effect on the inhibitory effect. Conclusions For patients with hypertension and dyslipidemia, the combination of dihydropyridine antihypertensive drugs and lovastatin is more likely to produce drug interactions. In order to avoid the occurrence of adverse reactions, LogP value should be selected larger, while the molecular weight, surface area smaller nifedipine and felodipine equality.