Lee Chong-Ki, Choi Jun-Shik, Choi Dong-Hyun
Department of Medical Management, Chodang University, Mooan, Republic of Korea.
College of Pharmacy, Chosun University, Pilmundero, Donggu, Gwangju, Republic of Korea.
Pharmacol Rep. 2015 Feb;67(1):44-51. doi: 10.1016/j.pharep.2014.08.005. Epub 2014 Aug 23.
This study aimed to investigate the effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats.
We determined the pharmacokinetic parameters of nifedipine and dehydronifedipine in rats after oral and intravenous administration of nifedipine without and with HMG-CoA reductase inhibitors. We evaluated the effect of HMG-CoA reductase inhibitors on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4.
Atorvastatin, fluvastatin, pravastatin and simvastatin inhibited CYP3A4 activities; inhibitory concentration (IC50) values were 47.0, 5.2, 15.0 and 3.3 μM, respectively. Simvastatin and fluvastatin increased the cellular uptake of rhodamine-123. The area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of oral nifedipine were significantly increased by fluvastatin and simvastatin, respectively, compared to control group. The total body clearance (CL/F) of nifedipine after oral administration with fluvastatin and simvastatin were significantly decreased compared to those of control. The metabolite-parent AUC ratio (MR) of nifedipine with fluvastatin and simvastatin were significantly decreased, which suggested that fluvastatin and simvastatin inhibited metabolism of nifedipine, respectively. The AUC0-∞ of intravenouse nifedipine with fluvastatin and simvastatin was significantly higher than that of the control group.
The increased bioavailability of nifedipine may be mainly due to inhibition of both P-gp in the small intestine and CYP3A subfamily-mediated metabolism of nifedipine in the small intestine and/or in the liver and to the reduction of the CL/F of nifedipine by fluvastatin and simvastatin.
本研究旨在探讨HMG-CoA还原酶抑制剂对硝苯地平在大鼠体内药代动力学的影响。
我们测定了在给予和未给予HMG-CoA还原酶抑制剂的情况下，大鼠口服和静脉注射硝苯地平后硝苯地平和脱氢硝苯地平的药代动力学参数。我们评估了HMG-CoA还原酶抑制剂对P-糖蛋白（P-gp）和细胞色素P450（CYP）3A4活性的影响。
阿托伐他汀、氟伐他汀、普伐他汀和辛伐他汀抑制CYP3A4活性；抑制浓度（IC50）值分别为47.0、5.2、15.0和3.3 μM。辛伐他汀和氟伐他汀增加了罗丹明-123的细胞摄取。与对照组相比，氟伐他汀和辛伐他汀分别显著增加了口服硝苯地平的血浆浓度-时间曲线下面积（AUC0-∞）和血浆峰浓度（Cmax）。与对照组相比，口服氟伐他汀和辛伐他汀后硝苯地平的总体清除率（CL/F）显著降低。硝苯地平与氟伐他汀和辛伐他汀的代谢物-母体AUC比值（MR）显著降低，这表明氟伐他汀和辛伐他汀分别抑制了硝苯地平的代谢。静脉注射硝苯地平与氟伐他汀和辛伐他汀的AUC0-∞显著高于对照组。
硝苯地平生物利用度的增加可能主要归因于小肠中P-gp的抑制以及小肠和/或肝脏中CYP3A亚家族介导的硝苯地平代谢的抑制，以及氟伐他汀和辛伐他汀对硝苯地平CL/F的降低。
