Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients

Abstract

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 (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 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.

Keywords: :

• Mycophenolic acid
• UGT1A9
• UGT2B7
• ABCC2
• polymorphism