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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Pharmacokinetics of the oral direct Renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of p-glycoprotein in the disposition of aliskiren.
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Pharmacokinetics of the oral direct Renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of p-glycoprotein in the disposition of aliskiren.

机译：口服直接肾素抑制剂阿利吉仑与地高辛，阿托伐他汀和酮康唑在健康受试者中的药代动力学：p-糖蛋白在阿利吉仑的治疗中的作用。

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This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.
机译：这项研究调查了直接肾素抑制剂阿利吉仑与P-糖蛋白和细胞色素P450 3A4（CYP3A4）调节剂之间的潜在药代动力学相互作用。 Aliskiren以高亲和力（K（m）2.1 micromol / L）刺激了重组杆状病毒感染的Sf9细胞的体外P-糖蛋白ATPase活性，并被具有中等亲和力的表达有机阴离子转运肽OATP2B1的HEK293细胞转运（K（m ）72微摩尔/升）。在健康受试者中进行的三项开放标签，多剂量研究调查了阿利吉仑300 mg与地高辛0.25 mg（n = 22），阿托伐他汀80 mg（n = 21）或酮康唑200 mg bid（n = 21）之间的药代动力学相互作用。与阿利吉仑合用会导致地高辛，阿托伐他汀，邻羟基阿托伐他汀和rho-羟基阿托伐他汀的AUC（tau）和C（max，ss）的变化<30％，表明与P-糖蛋白或CYP3A4底物。通过与阿托伐他汀（分别增加47％，P <.001）或酮康唑（分别增加76％，P <.001）并用最可能涉及转运蛋白（例如P-糖蛋白和有机阴离子转运）的机制，显着提高Aliskiren AUC（tau）肽可能通过肠壁中的代谢途径（例如CYP3A4）传播。这些结果表明阿利吉仑是P-糖蛋白抑制剂的底物，但不是抑制剂。基于在与阿托伐他汀和酮康唑合用期间，地高辛和阿托伐他汀的暴露量的微小变化和阿利吉仑的暴露量＜2倍的增加，作者得出结论，阿利吉仑与这些底物和/或底物之间具有临床相关药物相互作用的潜力P-糖蛋白/ CPY3A4 / OATP的抑制剂含量低。

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