Genetic and clinical determinants of mizoribine pharmacokinetics in renal transplant recipients.

ABSTRACT

AIM: 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. METHODS: 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. RESULTS: Extensive inter-individual MZR PK differences were reflected in the process of elimination (ke, CL/F, MRT and t1/2) and intestinal absorption (Cmax and Tmax), as well as in the dose-normalized exposure (AUC0-12h/D). From 146 SNPs within 39 genes screened, AUC0-12h/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-1 mg-1, p = 0.007). Recipients with SLC28A3 rs10868138 TT had lower t1/2 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 C0/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 AUC0-12h/D and t1/2, respectively. When additionally taking SCr into models, CREB1 and SLC28A3 genotypes explained 20.0% (p = 0.038) and 46.5% (p < 0.001) of AUC0-12h/D and t1/2 variability, respectively. CONCLUSION: CREB1 and SLC28A3 genotypes, as well as SCr, are identified as determinants in predicting inter-individual MZR PK differences in renal transplant recipients.