Choi Jin-Seok, Choi Jun-Shik, Choi Dong-Hyun
College of Pharmacy, Ajou University, Suwon, Republic of Korea.
Biopharm Drug Dispos. 2014 Oct;35(7):382-90. doi: 10.1002/bdd.1905. Epub 2014 Sep 8.
The purpose of this study was to investigate the possible effects of licochalcone A (a herbal medicine) on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and/or dehydronifedipine were determined after oral and intravenous administration of nifedipine to rats in the absence (control) and presence of licochalcone A (0.4, 2.0 and 10 mg/kg). The effect of licochalcone A on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was also evaluated. Nifedipine was mainly metabolized by CYP3A4. Licochalcone A inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50 ) of 5.9 μm. In addition, licochalcone A significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The area under the plasma concentration-time curve from time 0 to infinity (AUC) and the peak plasma concentration (Cmax ) of oral nifedipine were significantly greater and higher, respectively, with licochalcone A. The metabolite (dehydronifedipine)-parent AUC ratio (MR) in the presence of licochalcone A was significantly smaller compared with the control group. The above data could be due to an inhibition of intestinal CYP3A4 and P-gp by licochalcone A. The AUCs of intravenous nifedipine were comparable without and with licochalcone A, suggesting that inhibition of hepatic CYP3A4 and P-gp was almost negligible.
本研究旨在探讨甘草查尔酮A（一种草药）对大鼠体内硝苯地平及其主要代谢产物脱氢硝苯地平药代动力学的可能影响。在大鼠口服和静脉注射硝苯地平后，于无（对照组）和有甘草查尔酮A（0.4、2.0和10 mg/kg）存在的情况下，测定硝苯地平及/或脱氢硝苯地平的药代动力学参数。还评估了甘草查尔酮A对P-糖蛋白（P-gp）和细胞色素P450（CYP）3A4活性的影响。硝苯地平主要由CYP3A4代谢。甘草查尔酮A以浓度依赖性方式抑制CYP3A4酶活性，50%抑制浓度（IC50）为5.9 μmol/L。此外，甘草查尔酮A显著增强了过表达P-gp的MCF-7/ADR细胞中罗丹明-123的细胞内蓄积。甘草查尔酮A存在时，口服硝苯地平的血浆浓度-时间曲线下面积（AUC）和血浆峰浓度（Cmax）分别显著增大和升高。与对照组相比，甘草查尔酮A存在时代谢产物（脱氢硝苯地平）-母体AUC比值（MR）显著减小。上述数据可能是由于甘草查尔酮A对肠道CYP3A4和P-gp的抑制作用。有无甘草查尔酮A时静脉注射硝苯地平的AUC相当，表明对肝脏CYP3A4和P-gp的抑制作用几乎可以忽略不计。
