Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, Guangzhou, People's Republic of China.
Institute of Clinical Pharmacology, Sun Yat-sen University, Guangzhou, China.
Eur J Clin Pharmacol. 2021 Jan;77(1):45-53. doi: 10.1007/s00228-020-02936-7. Epub 2020 Aug 15.
Mizoribine (MZR) is an immunosuppressant for the prevention of allograft rejection in Asian countries, but the great variability in pharmacokinetics (PK) limits its clinical use. This study was to explore genetic and clinical factors that affect the MZR PK process.
Blood samples and clinical data were collected from 60 Chinese renal transplant recipients. MZR plasma concentration was measured at pre-dose (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h post-dose by high performance liquid chromatography with an ultraviolet detector. PK parameters were calculated by non-compartmental analysis. High-throughput sequenced single nucleotide polymorphism was applied screening possible genetic factors.
Extensive inter-individual MZR PK differences were reflected in the process of elimination (k, CL/F, MRT and t) and intestinal absorption (C and T), as well as in the dose-normalized exposure (AUC/D). From 146 SNPs within 39 genes screened, AUC/D was found higher in recipients with CREB1 rs11904814 TT than with G allele carriers (3.135 ± 0.928 versus 2.084 ± 0.379 μg h ml mg, p = 0.007). Recipients with SLC28A3 rs10868138 TT had lower t as compared to C allele carriers (0.728 ± 0.189 versus 0.951 ± 0.196 h, p = 0.001). Serum creatinine (SCr) explained 35.5% of C/D variability (p < 0.001). Pure effects of genotypes CREB1 and SLC28A3 were 13.7% (p = 0.004) and 17.5% (p = 0.001) for AUC/D and t, respectively. When additionally taking SCr into models, CREB1 and SLC28A3 genotypes explained 20.0% (p = 0.038) and 46.5% (p < 0.001) of AUC/D and t variability, respectively.
CREB1 and SLC28A3 genotypes, as well as SCr, are identified as determinants in predicting inter-individual MZR PK differences in renal transplant recipients.
吗替麦考酚酯（MZR）是亚洲国家预防同种异体移植排斥反应的免疫抑制剂，但药代动力学（PK）的巨大变异性限制了其临床应用。本研究旨在探讨影响 MZR PK 过程的遗传和临床因素。
收集 60 例中国肾移植受者的血样和临床资料。采用高效液相色谱-紫外检测法，在给药前（0 h）和给药后 0.5、1、2、3、4、5、6、8 和 12 h 测定 MZR 血浆浓度。采用非房室分析计算 PK 参数。高通量测序单核苷酸多态性用于筛选可能的遗传因素。
在消除（k、CL/F、MRT 和 t）和肠吸收（C 和 T）以及剂量标准化暴露（AUC/D）过程中，个体间 MZR PK 差异较大。在筛选出的 39 个基因中的 146 个 SNP 中，发现 CREB1 rs11904814 TT 携带者的 AUC/D 高于 G 等位基因携带者（3.135±0.928 比 2.084±0.379 μg·h·ml·mg，p=0.007）。与 C 等位基因携带者相比，SLC28A3 rs10868138 TT 携带者的 t 较短（0.728±0.189 比 0.951±0.196 h，p=0.001）。血清肌酐（SCr）解释了 C/D 变异性的 35.5%（p<0.001）。CREB1 和 SLC28A3 的纯基因型效应分别为 AUC/D 和 t 的 13.7%（p=0.004）和 17.5%（p=0.001）。当将 SCr 纳入模型时，CREB1 和 SLC28A3 基因型分别解释了 AUC/D 和 t 变异性的 20.0%（p=0.038）和 46.5%（p<0.001）。
在肾移植受者中，CREB1 和 SLC28A3 基因型以及 SCr 被确定为预测 MZR 个体间 PK 差异的决定因素。
