Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients
Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients
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DOI：
10.1080/00498250802488585
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发表时间：
2008-01-01
期刊：
影响因子：
1.8
通讯作者：
Cai, W.
中科院分区：
文献类型：
--
作者：
Zhang, W. -X.;Chen, B.;Cai, W.
目的探讨UGT1A9、UGT1A8、UGT2B7和ABCC2多态性对中国肾移植受者霉酚酸（MPA）及其代谢物酚型葡糖苷（MPAG）和酰基型葡糖苷（AcMPAG）药代动力学的影响。检测到UGT1A9-118(dT)9/10、UGT1A9 T-440C/C-331T、UGT1A8*3、UGT2B7 G211T、UGT2B7 C802T、ABCC2 C-24T、ABCC2 G1249A的单核苷酸多态性（SNP）。在肾移植后第30天，共有46名受者参加了药代动力学研究。MPA药代动力学特征的差异证实了患者之间MPA暴露的巨大差异。携带UGT1A9基因-118(dT)10等位基因的患者，经剂量调整后的MPA AUC6-12水平显著升高（T9 = 7.34 4.11 mg h ml-1 g-1; T9/T10 = 11.54 7.62 mg h ml-1 g-1; T10 = 11.89 8.76 mg h ml-1 g-1, p = 0.041）。剂量调整后的MPAG的AUC0-12和AUC6-12也有类似的趋势。携带ABCC2 G1249A杂合突变等位基因的患者AcMPAG的AUC6-12/D高于携带野生型的患者（p = 0.016）。基因分型的其他snp未引起MPA和MPAG药代动力学参数的显著变化。综上所述，UGT1A9-118(dT)10等位基因携带者体内MPA的肠肝再循环似乎更为广泛，携带ABCC2 G1249A基因型患者的AcMPAG暴露量高于野生型基因型患者。
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 AUC6-12 level of MPA was found in patients bearing the -118(dT)10 allele of the UGT1A9 gene (T9 = 7.34 4.11 mg h ml-1 g-1; T9/T10 = 11.54 7.62 mg h ml-1 g-1; and T10 = 11.89 8.76 mg h ml-1 g-1, p = 0.041). A similar trend was also observed for the dose-adjusted AUC0-12 and AUC6-12 of MPAG. Patients carrying the heterozygous mutant alleles of ABCC2 G1249A exhibited higher AUC6-12/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.