Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients

Abstract

Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance‐associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes ‐24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross‐sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0‐12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h. The wild‐type haplotype ABCC2 CGC had greater mycophenolic acid AUC0‐12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine‐mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.

Long-Term Outcomes after Conversion to a Belatacept-Based Immunosuppression in Kidney Transplant Recipients

“…2 However, the results remain consistent whatever the CNI used. 43 In conclusion, we demonstrated that a conversion to belatacept post-transplant is associated with a higher long-term graft survival and acceptable safety as compared with patients treated with a CNI-based immunosuppression. Conversion to belatacept after transplant might be considered as a therapeutic option in kidney recipients suffering from CNI nephrotoxicity or in patients with prolonged DGF or impaired graft function.…”

Sustained suppression of enterohepatic circulation of mycophenolic acid by antimicrobial‐associated diarrhea in a kidney transplant recipient with Crohn's disease: A case report

“… 2 , 3 MPAG and AcylMPAG are partially excreted in bile via multidrug resistance‐associated protein (MRP) 2. 4 , 5 MPAG excreted in bile is converted to MPA by β‐glucuronidase secreted by enteric bacteria and is reabsorbed. Since MPAG undergoes enterohepatic circulation via bile secretion, 6 , 7 a secondary peak emerges in the plasma concentration‒time profile 4 h or later after administration.…”