4种二氢吡啶类钙拮抗药对地塞米松诱导雌性大鼠CYP3A4酶活性的影响

Effects of Four Dihydropyridine Calcium Antagonists on CYP3A4 Enzyme Activity Induced By Dexamethasone in Female Rats

目的:研究二氢吡啶类钙离子拮抗药(DHPs)中非洛地平、尼卡地平、乐卡地平、硝苯地平对CYP3A4酶活性抑制作用大小,为临床了解DHPs发生药物相互作用的几率大小提供理论基础。方法:采用探针药物法,将经80 mg·kg-1·d-1地塞米松诱导3 d的SD雌性大鼠分为阴性对照组、阳性对照组、4种DHPs实验组,每组6只。氨苯砜为探针底物,HPLC法为检测手段,数据通过Win Non Lin药动学分析软件进行模型拟合处理,并通过配对t检验进行统计学分析。结果:阴性对照组与四种DHPs组、阳性对照组氨苯砜的AUC0-24、CL/F值比较有统计学意义(P<0.05)。4种DHPs对氨苯砜的代谢抑制作用大小分别为硝苯地平>尼卡地平>乐卡地平>非洛地平,但差异无统计学意义(P>0.05)。而统计学结果显示阳性对照组、4种DHPs组与阴性对照组的Cmax比较,差异无统计学意义(P>0.05)。结论:虽然不同DHPs对CYP3A4存在不同的抑制作用,但差异在体内表现并不显著,对于非主要通过CYP3A4代谢的共服药物不会产生影响。

Objective： To study the inhibition effects of four dihydropyridine calcium antagonists felodipine,nicardipine,lercanidipine and nifedipine on CYP3A4 enzyme to provide the theoretical basis for the understanding of the drug interactions between dihydropyridine calcium antagonists and other drugs. Methods： Using the probe drugs method,the SD female rats induced by 80 mg·kg^-1·d^-1 dexamethasone for three days were divided into the negative control group,positive control group,four DHPs groups with six ones in each. Dapsone was used as the probe substrate,and the concentration was determined by HPLC. Data analysis software Win Non Lin was used in the pharmacokinetic model fitting process and the paired t-test was used in the statistical analysis. Results： AUC0-24 and CL / F of dapsone in the negative control group showed statistically significant differences when compared with those in the four DHPs groups and the positive group（ P〈0. 05）. Although the inhibition effect of the four DHPs was in the order of nifedipine inhibition nicardipine lercanidipine felodipine,the difference was not statistically significant（ P〉0. 05）. Cmax of dapsone in the DHPs groups and the positive group had no statistically significant difference when compared with that in the negative control group（ P〉0. 05）. Conclusion： Although there are different inhibition effects on CYP3A4 among the four DHPs,the differences are not significant in vivo,and there is no influence on the combination drugs which is not mainly metabolized by CYP3A4.