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

Abstract

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 (AUC_0–2, 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.

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