Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
Clin Pharmacol Ther. 2011 Sep;90(3):414-22. doi: 10.1038/clpt.2011.130. Epub 2011 Jul 13.
In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 ± 73 vs. 354 ± 102 ml/min, P = 0.022) and 31% (479 ± 190 vs. 688 ± 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients.
体外研究已经确定环孢素和他克莫司是 CYP3A 抑制剂。在目前这项肾移植受者的研究中，我们使用静脉内和口服给予咪达唑仑作为药物探针，以评估研究药物在通常用于临床实践的剂量下是否对体内肝和首过 CYP3A 活性有不同的影响。全身和口服咪达唑仑清除率分别降低了 24%（269 ± 73 与 354 ± 102 ml/min，P = 0.022）和 31%（479 ± 190 与 688 ± 265 ml/min，P = 0.013），在环孢素治疗患者（n = 20）中低于匹配的他克莫司治疗患者（n = 20）。后者的咪达唑仑清除率与两个更大的非匹配他克莫司治疗患者队列（n = 58 和 n = 80）以及接受无钙调神经磷酸酶抑制剂方案的患者（n = 6）相似。这意味着接受环孢素治疗的患者体内肝和首过 CYP3A 活性明显低于接受他克莫司治疗的患者，表明在临床实践中通常使用的剂量下，环孢素在 CYP3A 抑制方面比他克莫司更强。这一观察结果在移植受者药物相互作用的背景下具有重要意义。
