Steady-state pharmacokinetics of mycophenolic acid in renal transplant patients: exploratory analysis of the effects of cyclosporine, recipients' and donors' ABCC2 gene variants, and their interactions.

PURPOSE: The study aims to evaluate the impact of recipients' and donors' polymorphisms in multidrug resistance-associated protein 2 (MRP2) gene ABCC2 -24C>T and 1249G>A on disposition of mycophenolic acid (MPA) and their interaction with cyclosporine (CsA) (compared to tacrolimus, TAC) in stable de novo adult renal transplant patients of Croatian origin.
METHODS: A total of 68 recipient-donor pairs were genotyped. Steady-state pharmacokinetics of MPA was assessed by the model-independent method.
RESULTS: Adjusted for MPA formulation, renal function, type of calcineurin inhibitor and recipients' and donors' genotypes at the two loci, donors' A-allele at 1249G>A was associated with a reduced peak (29%) and early (AUC0-2, 33%) exposure and increased MPA clearance (26%). Donors' A-allele combined with CsA was associated with 78% higher MPA clearance, 49% lower early and 48% lower total exposure as compared to wild type homozygosity + TAC. Recipients' SNPs per se did not reflect on MPA disposition. However, A-allele at 1249G>A + CsA (compared to wild type + TAC) was associated with a numerically greater increase in MPA clearance (59 vs. 41%), reduction in total exposure (36 vs. 27%) and increase in absorption rate (C max/AUC) (56 vs. 37%) than observed for the main effect of CsA. Less pronounced effects were observed for the combination of variant allele at -24C>T and CsA.
CONCLUSION: Considering MPA disposition, data indicate: donors' ABCC2 1249G>A polymorphism increases clearance and reduces exposure; CsA increases clearance and reduces exposure by inhibiting MRP2 in the gut, the liver, and the kidney; donors' ABCC2 1249G>A polymorphism enhances the renal CsA effect, while recipients' polymorphism seems to enhance the liver and the gut CsA effects.