Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine
Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine
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DOI：
10.1016/j.clpt.2004.03.010
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发表时间：
2004-08-01
影响因子：
6.7
通讯作者：
Schneck, DW
中科院分区：
文献类型：
--
作者：
Simonson, SG;Raza, A;Schneck, DW
背景：环孢素（INN，环孢素）会增加所有他汀类药物的全身暴露。因此，在一项开放标签试验中评估了瑞舒伐他汀的药代动力学参数，该试验涉及稳定的心脏移植受者（移植后大于或等于6个月），采用包括环孢素的抗排斥方案。瑞舒伐他汀已被证明是人肝脏转运蛋白有机阴离子转运多肽 C (OATP-C) 的底物。抑制这种转运蛋白可以增加瑞舒伐他汀的血浆浓度。因此，还检查了环孢素对表达 OATP-C 的细胞摄取瑞舒伐他汀的影响。方法：对 10 名受试者服用 10 mg 瑞舒伐他汀 10 天进行评估；然后对其中 5 名患者服用 20 毫克瑞舒伐他汀 10 天进行评估。将瑞舒伐他汀稳态面积、从 0 至 24 小时的血浆浓度-时间曲线 [AUC(0-24)] 和最大观察血浆浓度 (C-max) 与对照值（来自服用 10 mg 瑞舒伐他汀的 21 名健康志愿者的历史数据）进行比较。还通过使用放射性标记的瑞舒伐他汀（含或不含环孢素）研究了 OATP-C 转染的非洲爪蟾卵母细胞对瑞舒伐他汀的摄取。 结果：在服用 10 mg 瑞舒伐他汀的移植受者中，稳态 AUC(0-24) 和 C-max 的几何平均值和变异百分比系数分别为 284 ng (.) h/mL (31.3%) 和 48.7 ng/mL (47.2%)。在对照中，这些值分别为 40.1 ng (.) h/mL (39.4%) 和 4.58 ng/mL (46.9%)。与对照值相比，移植受者的AUC(0-24)和C-max分别增加了7.1倍和10.6倍。在服用 20 mg 瑞舒伐他汀的移植受者中，这些参数的增加幅度小于剂量比例。瑞舒伐他汀对环孢素血药浓度没有影响。体外结果表明，瑞舒伐他汀是 OATP-C 介导的肝脏摄取的良好底物（结合常数，8.5 +/- 1.1 mumol/L），而环孢素是该过程的有效抑制剂（50%抑制常数，当瑞舒伐他汀浓度为 5 μmol/L 时，为 2.2 +/- 0.4 mumol/L）。结论：移植受者中瑞舒伐他汀暴露量显着增加包括环孢素在内的抗排斥疗法。环孢素抑制OATP-C介导的瑞舒伐他汀肝摄取可能是药物相互作用的机制。瑞舒伐他汀与环孢素合用需谨慎。
Background: Cyclosporine (INN, ciclosporin) increases the systemic exposure of all statins. Therefore rosuvastatin pharmacokinetic parameters were assessed in an open-label trial involving stable heart transplant recipients (greater than or equal to6 months after transplant) on an antirejection regimen including cyclosporine. Rosuvastatin has been shown to be a substrate for the human liver transporter organic anion transporting polypeptide C (OATP-C). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. Therefore the effect of cyclosporine on rosuvastatin uptake by cells expressing OATP-C was also examined.Methods: Ten subjects were assessed while taking 10 mg rosuvastatin for 10 days; 5 of these were then assessed while taking 20 mg rosuvastatin for 10 days. Rosuvastatin steady-state area tinder the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] and maximum observed plasma concentration (C-max) were compared with values in controls (historical data from 21 healthy volunteers taking 10 mg rosuvastatin). Rosuvastatin uptake by OATP-C-transfected Xenopus oocytes was also studied by use of radiolabeled rosuvastatin with and without cyclosporine.Results: In transplant recipients taking 10 mg rosuvastatin, geometric mean values and percent coefficient of variation for steady-state AUC(0-24) and C-max were 284 ng (.) h/mL (31.3%) and 48.7 ng/mL (47.2%), respectively. In controls, these values were 40.1 ng (.) h/mL (39.4%) and 4.58 ng/mL (46.9%), respectively. Compared with control values, AUC(0-24) and C-max were increased 7.1-fold and 10.6-fold, respectively, in transplant recipients. In transplant recipients taking 20 mg rosuvastatin, these parameters increased less than dose-proportionally. Rosuvastatin had no effect on cyclosporine blood concentrations. The in vitro results demonstrate that rosuvastatin is a good substrate for OATP-C-mediated hepatic uptake (association constant, 8.5 +/- 1.1 mumol/L) and that cyclosporine is an effective inhibitor of this process (50% inhibition constant, 2.2 +/- 0.4 mumol/L when the rosuvastatin concentration was 5 mumol/L).Conclusions: Rosuvastatin exposure was significantly increased in transplant recipients on an antirejection regimen including cyclosporine. Cyclosporine inhibition of OATP-C-mediated rosuvastatin hepatic uptake may be the mechanism of the drug-drug interaction. Coadministration of rosuvastatin with cyclosporine needs to be undertaken with caution.