흰쥐에서 HMG-CoA환원효소억제제가 니페디핀 및 그대사체인 디히드로니페디핀의 약물동태에 미치는 영향

Abstract

항콜레스테롤제와 항고혈압치료제인 니페디핀과의 병용투여가 순환기 질환 예방 및 치료를 위해서 처방되는 경우가 많다. 그러므로 이에 대한 상호작용을 연구하고자 흰쥐에 니페디핀 (경구; 10 mg/kg, 정맥; 2.5 mg/kg)과 HMG-CoA환원효소 억제제인 아톨바스타틴 (0.3, 1.0 mg/kg), 프루바스타틴 (0.3, 1.0 mg/kg), 프라바스타틴 (0.3, 1.0 mg/kg)과 심바스타틴 (0.3, 1.0 mg/kg)을 병용 경구 및 정맥 투여한 후 니페디핀 및 그 주요 대사체인 디히드로니페디핀의 약물동태학적 변수들을 대조군과 비교 검토하였다. 그리고 HMG-CoA환원효소 억제제인 아톨바스타틴, 프루바스타틴, 프라바스타틴과 심바스타틴이 cytochromeP450(CYP)3A4활성과 P-glycoprotein(P-gp)의 활성에 미치는 영향도 평가 하였다. 프루바스타틴과 심바스타틴이 CYP3A4활성과 P-gp의 활성을 유의성 있게 억제시켰다. 프루바스타틴 또는 심바스타틴과 각각 병용 투여시 니페디핀의 약물동태학적 변수는 유의성 있게 변화하였다. 대조군에 비해 프루바스타틴 (1.0 mg/kg) 또는 심바스타틴 (0.3, 1.0 mg/kg)과의 병용투여군에서 니페디핀의 혈장농도곡선하면적 (AUC0-∞)과 최고혈중농도 (Cmax)는 각각 유의성 (P < 0.05, P < 0.01) 있게 증가시켰으나, 아톨바스타틴과 프라바스타틴과 병용투여군에서는 증가시켰으나 유의성은 없었다. HMG-CoA환원효소 억제제의 저농도(0.3 mg/kg) 에서는 증가는 시켰으나 유의성은 없었다. 프루바스타틴 또는 심바스타틴(0.3, 1.0 mg/kg)과의 병용투여군에서 니페디핀의 전신클리어런스 (CL/F)는 유의성 (P < 0.05, P < 0.01) 있게 각각 감소되었다. 절대적생체이용률 (AB)도 대조군에 비해 각각 유의성 (P < 0.05) 있게 증가되었다. 프루바스타틴 (1.0 mg/kg) 또는 심바스타틴 (1.0 mg/kg)과 니페디핀을 병용투여한군에서 대조군에 비해 대사체인 디히드로니페디핀의 혈장농도곡선하면적 (AUC0-∞)이 유의성 (P < 0.05) 있게 증가되었다. 그리고 프루바스타틴 또는 심바스타틴과 병용투여군에서 니페디핀의 대사율 (MR)을 유의성 (P < 0.05) 있게 감소시켰다. 정맥투여군에서는 아톨바스타틴, 프루바스타틴, 프라바스타틴과 심바스타틴은 니페디핀의 약동학적 변수에는 거의 영향을 주지 못하였다. 본 연구에서 항콜레스테롤제인 프루바스타틴 또는 심바스타틴을 각각 고혈압치료제인 니페디핀과 병용투여 하였을 때 경구투여된 니페디핀의 생체이용률이 유의성 있게 증가된 것은 프루바스타틴 및 심바스타틴에 의해서 주로 소장에 존재하는 P-gp억제에 의한 흡수증가와 주로 소장과 간장에 존재하는 CYP3A 억제에 의한 니페디핀의 초회통과효과 (대사)감소와 전신클리어런스 감소에 기인한 것으로 사료된다. 항콜레스테롤제인 HMG-CoA환원효소 억제제와 (특히 프루바스타틴과 심바스타틴) 항고혈압치료제인 니페디핀과의 병용투여시 이들의 상호작용을 고려하는 것이 중요하다고 사료 되어진다.|The present study was designed to investigate the effects of HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, pravastatin, simvastatin) on the pharmacokinetics of nifedipine and its active metabolite, dehydronifedipine in rats. Pharmacokinetic parameters of nifedipine and dehydronifedipine in rats were determined after oral and intravenous administration of nifedipine without and with HMG-CoA reductase inhibitors (0.3 or 1.0 mg/kg). The effect of HMG-CoA reductase inhibitors on p-glycoprotein (P-gp) and CYP3A4 activity were also evaluated. Atorvastatin, fluvastatin, pravastatin and simvastatin inhibited CYP3A4 activities with IC50 values of 47.0, 5.4, 14.8 and 3.1 μM, respectively. Simvastatin and fluvastatin (3-10, 100 μM) enhanced the cellular uptake of rhodamine-123 in a concentration-dependent manner, suggesting that P-gp activity was inhibited by fluvastatin and simvastatin. The area under the plasma concentration-time curve (AUC0–∞) and the peak plasma concentration (Cmax) of nifedipine were significantly (p<0.05) increased respectively by fluvastatin (1.0 mg/kg) compared to those of control. The area under the plasma concentration-time curve (AUC0–∞) and the peak plasma concentration (Cmax) of nifedipine were significantly (p<0.05, p<0.01) increased respectively by simvastatin (0.3 and 1.0 mg/kg) compared to those of control. The area under the plasma concentration-time curve (AUC0–∞) and the peak plasma concentration (Cmax) of nifedipine were increased respectively by atovastatin and pravastatin compared to those of control, but these were not singnificant. All pharmacokinetic parameters of nifedipine were not affected by low dosage of HMG-CoA reductase inhibitors (0.3 mg/kg). The total body clearance (CL/F) of nifedipine after oral administration with fluvastatin (1.0 mg/kg) was significantly decreased (by 50.6%) compared to that of control. The total body clearance (CL/F) of nifedipine after oral administration with simvastatin (0.3 and 1.0 mg/kg) was significantly decreased (by 46.9 and 55.7%) compared to that of control. Consequently, the absolute bioavailability (AB) of nifedipine after oral administration with fluvastatin was significantly increased (by 42.4%) compared to that of control. The absolute bioavailability (AB) of nifedipine after oral administration with simvastatin was significantly increased (by 41.1 and 51.9%) compared to that of control.

The absolute bioavailability (AB) of nifedipine after oral administration with atovastatin and pravastatin was increased compared to that of control, but this was not significant. The relative bioavailability (RB) of nifedipine was 1.11-to 1.51-fold greater than that of the control by HMG-CoA reductase inhibitors. The area under the plasma concentration-time curve (AUC0–∞) of dehydronifedipine were significantly (p<0.05) increased respectively by fluvastatin and simvastatin (1.0 mg/kg) compared to those of control. The metabolite-parent AUC ratio (MR) of nifedipine with fluvastatin and simvastatin was significantly decreased respectively by 16.0 and 18.4%, suggesting that metabolism of nifedipine in the small intestine and/or liver was inhibited by fluvastatin 1.0 mg/kg) and simvastatin (0.3 and 1.0 mg/kg). After intravenous administration of nifedipine with HMG-CoA-reductase inhibitor, the AUC of nifedipine increased, but was not statistically significant. The CLt and t1/2 values of nifedipine tend to decrease, but was not statistically significant. This suggests that the effects of HMG-CoA-reductase inhibitor on the inhibition of hepatic metabolism of nifedipine via CYP3A4 were almost negligible. In conclusion, the enhanced bioavailability of nifedipine might be mainly due to inhibition of P-gp in the small intestine and CYP3A subfamily-mediated metabolism of nifedipine in the small intestine and/or liver and to reduction of the CL/F of nifedipine by fluvastatin and simvastatin. Since the present study raised awareness of potential drug interactions by concomitant use of nifedipine with HMG-CoA-reductase inhibitors, this result has to be further evaluated for dosage regimen of nifedipine in clinical studies.

Keywords: Nifedipine; dehydronifedipine; HMG-CoA reductase inhibitors; pharmacokinetics; bioavailability; AUC0–∞; Cmax ; total body clearance; P-gp; CYP3A subfamily; rats