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

• Published in: European journal of clinical pharmacology Vol. 73; no. 9; pp. 1129 - 1140
• Main Authors: Božina, N., Lalić, Z., Nađ-Škegro, S., Borić-Bilušić, A., Božina, T., Kaštelan, Ž., Trkulja, V.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2017; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Alleles; Biomedical and Life Sciences; Biomedicine; Calcineurin; Calcineurin Inhibitors - pharmacology; Cyclosporine - pharmacology; Cyclosporins; Drug Interactions; Exposure; Female; Gastrointestinal tract; Gene polymorphism; Genotype; Genotype & phenotype; Genotypes; Homozygosity; Humans; Immunosuppressive Agents - pharmacokinetics; Kidney diseases; Kidney Transplantation; Liver; Male; Middle Aged; Multidrug resistance; Multidrug Resistance-Associated Proteins - genetics; Mycophenolic acid; Mycophenolic Acid - pharmacokinetics; Organ donors; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Polymorphism, Single Nucleotide; Renal function; Single-nucleotide polymorphism; Tacrolimus; Tacrolimus - pharmacology; Tissue Donors; Transplants & implants; Young Adult; Renal transplantation; ABCC2 protein; Immunosuppression; Mycophenolic acid; Cyclosporine; Tacrolimus
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-017-2285-4

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.