The association of the UGT1A8, SLCO1B3 and ABCC2/ABCG2 genetic polymorphisms with the pharmacokinetics of mycophenolic acid and its phenolic glucuronide metabolite in Chinese individuals

BackgroundThis study aimed to evaluate the effect of UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A polymorphisms on the pharmacokinetics (PKs) of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) in healthy Chinese volunteers and in stable renal transplant patients.MethodsThe data were extracted from comparative bioavailability studies conducted in 42 healthy individuals and 37 renal transplant patients. A complete PK profile was obtained over 48 h for healthy volunteers and over 12 h for the transplant patients. The MPA/MPAG plasma concentrations were measured by HPLC. The genotypes were determined using either the Taqman probe technique or direct sequencing. A multivariate analysis was used to assess the effect of the genotypes (UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A) and other covariates (age, weight, height, calculated creatinine clearance, serum albumin, haemoglobin and drug comedication) on the AUC4–12 and AUC0–12 for MPA and MPAG in the healthy volunteers and patients.ResultsIn the healthy volunteers, the dose-adjusted geometric means (GM) of the MPA AUC4–12 in individuals with the SLCO1B3 334T allele were 30.4% lower than those values in the 334G homozygote carriers (P < 0.05); in the transplant patients, the steroid dose was associated with a negative effect on the AUC of MPAG (P < 0.03) and weight was associated with a negative effect on the AUC for MPA in the healthy volunteers and patients (P < 0.03). No other significant effect of genotype or of the other studied variables on AUC4–12 or AUC0–12 of MPA/MPAG was found in the healthy volunteers or patients.ConclusionsThe PKs of MPA is affected by the SLCO1B3 polymorphism in healthy Chinese individuals. The absence of an effect of SLCO1B3 polymorphisms in transplant patients may be due to the co-administration of cyclosporine (CsA). Concomitant steroid dose and weight are two important covariates of the AUC of MPA and MPAG, which should be taken into account in clinical use. Further confirmatory in vivo studies are needed.

► UGT1A8*2, SLCO1B3 T334G, ABCC2 C24T and ABCG2 C421A polymorphisms were genotyped.
► PKs of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) were profiled.
► Impact of genetic polymorphisms was examined in both healthy subjects and patients.
► The SLCO1B3 T334G polymorphism only affected the PK of MPA in healthy subjects.
► Concomitant steroid dose and weight are covariates of the exposure of MPA and MPAG.