In Vivo CYP3A4 Activity, CYP3A5 Genotype, and Hematocrit Predict Tacrolimus Dose Requirements and Clearance in Renal Transplant Patients
In Vivo CYP3A4 Activity, CYP3A5 Genotype, and Hematocrit Predict Tacrolimus Dose Requirements and Clearance in Renal Transplant Patients
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DOI：
10.1038/clpt.2012.109
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发表时间：
2012-09-01
影响因子：
6.7
通讯作者：
Kuypers, D. R.
中科院分区：
文献类型：
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作者：
de Jonge, H.;de Loor, H.;Kuypers, D. R.
他克莫司通过CYP 3A 4和CYP 3A 5代谢，其特征是治疗指数较窄，药代动力学变化较大。这项在59例肾移植患者中进行的横断面研究调查了体内CYP 3A 4活性（使用咪达唑仑作为药物探针进行评估）、CYP 3A 5基因型和他克莫司药代动力学之间的关系，同时考虑了他克莫司分布的其他潜在决定因素。体内CYP 3A 4活性和CYP 3A 5基因型解释了他克莫司剂量需求和清除率变异性的56-59%，分别贡献了25%和30%。红细胞压积解释了额外的4- 14%。这些数据表明，CYP 3A 4和CYP 3A 5介导的他克莫司代谢是他克莫司体内分布的主要决定因素，并解释了临床观察到的他克莫司药代动力学个体间变异性高的主要原因。此外，这些数据提供了一个潜在的基础，一个全面的方法来预测他克莫司剂量的需求，在个别患者，因此提供了一个策略，以适应移植受体的免疫抑制治疗。
Tacrolimus is metabolized by CYP3A4 and CYP3A5 and is characterized by a narrow therapeutic index and highly variable pharmacokinetics. This cross-sectional study in 59 renal transplant patients investigated the relationship among in vivo CYP3A4 activity (assessed using midazolam as a drug probe), CYP3A5 genotype on the one hand, and tacrolimus pharmacokinetics on the other hand, taking into account other potential determinants of tacrolimus disposition. In vivo CYP3A4 activity and CYP3A5 genotype explain 56-59% of variability in tacrolimus dose requirements and clearance, contributing similar to 25 and 30%, respectively. Hematocrit explains an additional 4-14%. These data indicate that CYP3A4- and CYP3A5-mediated tacrolimus metabolisms are major determinants of tacrolimus disposition in vivo and explain a substantial part of the clinically observed high interindividual variability in tacrolimus pharmacokinetics. Furthermore, these data provide a potential basis for a comprehensive approach to predicting tacrolimus dose requirement in individual patients and hence provide a strategy to tailor immunosuppressive therapy in transplant recipients.