Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea.
Transplantation. 2013 Mar 27;95(6):828-34. doi: 10.1097/TP.0b013e31827eef57.
We prospectively studied renal transplant recipients receiving tacrolimus to determine the relationship between the CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms and the pharmacokinetics (PK) and pharmacodynamics (PD) of tacrolimus and its metabolites.
Renal transplant recipients receiving tacrolimus were genotyped for CYP3A44, CYP3A45, CYP3A418, CYP3A53, ABCB1 c.1236C→T, ABCB1 c.2677G→A/T, and ABCB1 c.3435C→T. Dose-adjusted trough concentration (C0) of tacrolimus and its metabolites (M-I and M-III) and PK and PD (T-cell and monocyte subsets) were determined on transplantation days -2, 5, 30, and 90 and correlated with the corresponding genotypes.
The dose-adjusted C0 of tacrolimus and its metabolites and AUC0-12 were significantly higher and the mean fluorescence intensity (MFI) of HLA/DR in monocytes was significantly lower in patients with CYP3A5*3/3 than in patients with CYP3A51/1 or CYP3A51/3. However, there was no significant difference in the dose-adjusted C0 of tacrolimus and its metabolites, PK and PD among the ABCB1 genotypes. The MFI of HLA/DR in monocytes showed a significant negative correlation with dose-adjusted C0 of tacrolimus and its metabolites and AUC0-12. In a multiple regression analysis, the presence of the CYP3A53/*3 genotype was a significant independent variable determining the dose-adjusted C0 of tacrolimus and its metabolites, AUC0-12, and the MFI of HLA/DR in monocytes.
This study demonstrates that the CYP3A5 genetic polymorphisms are associated with the individual differences in PK and PD as well as in C0 of tacrolimus and its metabolites. The MFI of HLA/DR in monocytes might be considered to be a significant tool for monitoring tacrolimus efficacy.
我们前瞻性地研究了接受他克莫司治疗的肾移植受者，以确定 CYP3A4、CYP3A5 和 ABCB1 基因多态性与他克莫司及其代谢物的药代动力学（PK）和药效学（PD）之间的关系。
对接受他克莫司治疗的肾移植受者进行 CYP3A44、CYP3A45、CYP3A418、CYP3A53、ABCB1 c.1236C→T、ABCB1 c.2677G→A/T 和 ABCB1 c.3435C→T 的基因分型。在移植前 2 天、第 5 天、第 30 天和第 90 天测定他克莫司及其代谢物（M-I 和 M-III）的剂量调整后的谷浓度（C0）和 PK 和 PD（T 细胞和单核细胞亚群），并与相应的基因型相关联。
与 CYP3A5*1/1 或 CYP3A51/3 患者相比，CYP3A53/3 患者的他克莫司及其代谢物的剂量调整后 C0 和 AUC0-12 显著升高，单核细胞中 HLA/DR 的平均荧光强度（MFI）显著降低。然而，ABCB1 基因型之间的他克莫司及其代谢物的剂量调整后 C0、PK 和 PD 无显著差异。单核细胞中 HLA/DR 的 MFI 与他克莫司及其代谢物的剂量调整后 C0 和 AUC0-12 呈显著负相关。在多元回归分析中，CYP3A53/*3 基因型的存在是决定他克莫司及其代谢物的剂量调整后 C0、AUC0-12 和单核细胞中 HLA/DR 的 MFI 的显著独立变量。
本研究表明，CYP3A5 基因多态性与他克莫司及其代谢物的 PK 和 PD 以及他克莫司及其代谢物的 C0 个体差异有关。单核细胞中 HLA/DR 的 MFI 可能被认为是监测他克莫司疗效的重要工具。
