Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients.
Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients.
复制标题
DOI：
10.1007/s40262-013-0069-2
复制
发表时间：
2013-09
影响因子：
4.5
通讯作者：
Akhlaghi F
中科院分区：
文献类型：
--
作者：
Ogasawara K;Chitnis SD;Gohh RY;Christians U;Akhlaghi F
他克莫司是一种免疫抑制剂，用于预防肾移植受者的移植排斥反应。它表现出狭窄的治疗指数和较大的药代动力学变异性。他克莫司主要经细胞色素P450（CYP）3A 4和3A 5代谢，并通过ATP结合盒（ABC）转运蛋白（如ABCB 1基因编码的P-糖蛋白（P-gp））外排。CYP 3A 5 *3对他克莫司药代动力学的影响已得到充分表征。另一方面，其他基因多态性的贡献是有争议的。此外，P-gp以外的其他外排转运蛋白参与他克莫司处置尚不确定。本研究旨在探讨CYP 3A和外排转运蛋白基因多态性对他克莫司药代动力学的影响。共500个他克莫司的血液浓度从102名成人稳定的肾移植受者被纳入分析。检测CYP 3A 4和CYP 3A 5基因多态性，以及外排转运蛋白P-gp（ABCB 1）、多药耐药相关蛋白（MRP 2/ABCC 2）和乳腺癌耐药蛋白（BCRP/ABCG 2）基因多态性。对于ABCC 2基因，单倍型确定如下：H1（野生型）、H2（1249 G>A）、H9（3972 C>T）和H12（− 24 C>T和3972 C>T）。采用非线性混合效应模型进行群体药代动力学分析。分析显示，CYP 3A 5表达者（CYP 3A 5 *1携带者）和MRP 2高活性组（ABCC 2 H2/H2和H1/H2）分别使他克莫司的剂量标准化谷浓度降低2.3倍（p<0.001）和1.5倍（p=0.007）。他克莫司的药代动力学最好使用具有一级吸收和吸收滞后时间的二室模型来描述。在群体药代动力学分析中，CYP 3A 5表达者和MRP 2高活性组被确定为他克莫司表观清除率的显著协变量，表示为20.7 ×（年龄/50）−0.78 × 2.03（CYP 3A 5表达者）× 1.40（MRP 2高活性组）。没有其他CYP 3A 4、ABCB 1和ABCG 2多态性与他克莫司的表观清除率相关。这是首次报道MRP 2/ABCC 2以单倍型特异性方式对他克莫司的药代动力学具有重要影响。ABCC 2和CYP 3A 5基因型的测定可能有助于更准确地调整他克莫司剂量。
Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in the kidney allograft recipients. It exhibits a narrow therapeutic index and a large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5, and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporter than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus. A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes as well as the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (−24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. Analyses revealed that CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high activity group (ABCC2 H2/H2 and H1/H2) decreased the dose-normalized trough concentration of tacrolimus by 2.3-fold (p<0.001) and 1.5-fold (p=0.007), respectively. The pharmacokinetics of tacrolimus was best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7 × (Age/50)−0.78 × 2.03 (CYP3A5 expressers) × 1.40 (MRP2 high activity group). No other CYP3A4, ABCB1 and ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus. This is the first report that MRP2/ABCC2 has crucial impacts on the pharmacokinetics of tacrolimus in a haplotype specific manner. Determination of ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.