Zhang W-X, Chen B, Jin Z, Yu Z, Wang X, Chen H, Mao A, Cai W
Institute of Clinical Pharmacology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Xenobiotica. 2008 Nov;38(11):1422-36. doi: 10.1080/00498250802488585.
The aim was to investigate the effect of UGT1A9, UGT1A8, UGT2B7 and ABCC2 polymorphism on the pharmacokinetics of mycophenolic acid (MPA) and its metabolites phenolic glucuronide (MPAG) and acyl glucuronide (AcMPAG) in Chinese renal transplant recipients. Single nucleotide polymorphisms (SNP) in UGT1A9-118(dT)(9)/(10), UGT1A9 T-440C/C-331T, UGT1A8*3, UGT2B7 G211T, UGT2B7 C802T, ABCC2 C-24T, and ABCC2 G1249A were detected. A total of 46 recipients were enrolled in the pharmacokinetics study at day 30 after kidney transplantation. Differences in the MPA pharmacokinetic profiles confirmed large inter-patient variation of MPA exposure. A statistical significant increase in the dose-adjusted AUC(6-12) level of MPA was found in patients bearing the -118(dT)(10) allele of the UGT1A9 gene (T(9) = 7.34 +/- 4.11 mg h ml(-1) g(-1); T(9)/T(10) = 11.54 +/- 7.62 mg h ml(-1) g(-1); and T(10) = 11.89 +/-8.76 mg h ml(-1) g(-1), p = 0.041). A similar trend was also observed for the dose-adjusted AUC(0-12) and AUC(6-12) of MPAG. Patients carrying the heterozygous mutant alleles of ABCC2 G1249A exhibited higher AUC(6-12)/D of AcMPAG than those with wild-type genotype (p = 0.016). The other SNPs that were genotyped did not cause any significant variation in MPA and MPAG pharmacokinetic parameters. In conclusion, the enterohepatic recirculation of MPA in the patients seems to be more extensive in UGT1A9-118(dT)(10) allele carriers, and the exposure of AcMPAG is higher in patients carrying ABCC2 G1249A genotype than those with wild-type genotype.
本研究旨在探讨尿苷二磷酸葡萄糖醛酸转移酶1A9（UGT1A9）、尿苷二磷酸葡萄糖醛酸转移酶1A8（UGT1A8）、尿苷二磷酸葡萄糖醛酸转移酶2B7（UGT2B7）和ATP结合盒转运体C2（ABCC2）基因多态性对中国肾移植受者霉酚酸（MPA）及其代谢产物酚葡糖苷酸（MPAG）和酰基葡糖苷酸（AcMPAG）药代动力学的影响。检测了UGT1A9 - 118(dT)(9)/(10)、UGT1A9 T - 440C/C - 331T、UGT1A8*3、UGT2B7 G211T、UGT2B7 C802T、ABCC2 C - 24T和ABCC2 G1249A的单核苷酸多态性（SNP）。共有46例受者在肾移植术后第30天纳入药代动力学研究。MPA药代动力学曲线的差异证实了患者间MPA暴露存在较大差异。携带UGT1A9基因 - 118(dT)(10)等位基因的患者中，MPA的剂量校正AUC(6 - 12)水平有统计学意义的升高（T(9) = 7.34 ± 4.11 mg·h·ml⁻¹·g⁻¹；T(9)/T(10) = 11.54 ± 7.62 mg·h·ml⁻¹·g⁻¹；T(10) = 11.89 ± 8.76 mg·h·ml⁻¹·g⁻¹，p = 0.041）。MPAG的剂量校正AUC(0 - 12)和AUC(6 - 12)也观察到类似趋势。携带ABCC2 G1249A杂合突变等位基因的患者比野生型基因型患者的AcMPAG的AUC(6 - 12)/D更高（p = 0.016）。其他基因分型的SNP在MPA和MPAG药代动力学参数上未引起任何显著差异。总之，UGT1A9 - 118(dT)(10)等位基因携带者中MPA的肠肝循环似乎更广泛，携带ABCC2 G1249A基因型的患者比野生型基因型患者的AcMPAG暴露更高。
