engleski

Influence of ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Croatian renal allograft recipients

Background. Mycophenolic acid (MPA) displays variable pharmacokinetics (PK). It is metabolized by UGTs to inactive 7-O-MPA-glucuronide (MPAG). MPA and MPAG are subject to enterohepatic recirculation. Biliary and kidney excretion of MPA/MPAG involves several transporters, including multidrug resistant protein-2 (MRP2) coded by polymorphic gene ABCC2. MRP2 serves as an efflux carrier of drug conjugates and many nonconjugated compounds in organs including intestine, liver and kidney. We assessed steady-state PK of MPA in renal allograft recipients in respect to donor and recipient ABCC2 genotypes. Patients and methods. Patients (n=68, men=36, age 15-72 years) were treated with mycophenolate sodium (MY) (n= 45, 2x720 mg/day) or mycophenolate mofetil (MMF) (n=23, 2x500 to 2x1000 mg/day), and all received cyclosporine (n=43) or tacrolimus (n= 25) and corticosteroids. Blood samples were taken during one dosing-interval (12 hrs) at 0, 0.5, 1, 2, 3, 8, and 12 h after the morning dose. PK parameters (ln- transformed) were analyzed by fitting generalized linear models with independents: age, sex, body mass index, treatment (MY or MMF), calcineurin inhibitor type, donor and recipient genotypes at two polymorphic loci (ABCC2 C-24T, G1249A). Results. Pharmacokinetic parameters for MPA are: Cmax, ss (ng/mL per mg dose) 16.08.7 ; Tmax, ss (hrs) 2 (0.2-12) ; AUC, ss (ng*h/mL per mg dose) 52.327.6 ; Cmin, ss (ng/mL per mg dose) 1.71.5 ; Trough 1 (time 0) (ng/mL per mg dose) 3.62.9 ; Trough 2 (time 12) 2.62.6. Regarding the donor ABCC2 genotypes: T- allele (C-24T) was independently associated with lower Cmin (geometric mean ratio, GMR=0.61, 90% CI 0.40-0.92), lower trough 1 (GMR=0.54, 0.35-0.83), lower trough 2 (GMR 0.61, 0.37-0.99) and greater MPA concentration oscillations (GMR=1.88, 1.09-3.23). Regarding the recipient genotypes: A-allele (G1249A) was independently associated with lower Cmin (GMR=0.55, 0.36-0.66), lower trough 2 (GMR=0.54, 0.32-0.90) and greater % swing (GMR=1.85, 1.05-3.28). Conclusion. The pharmacokinetics of MPA is affected by the donor and recipient ABCC2 polymorphisms.

mycophenolic acid; pharmacokinetics; MRP2/ABCC2; pharmacogenetics

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