Influence of ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Croatian renal allograft recipients (CROSBI ID 634239)
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Podaci o odgovornosti
Božina, Nada ; Lalić, Zdenka ; Nađ-Skegro, Sandra ; Lovrić, Mila ; Trkulja, Vladimir ; Pasini, Josip
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) 16.08.7 ; Tmax, ss (hrs) 2 (0.2-12) ; AUC, ss (ng*h/mL per mg dose) 52.327.6 ; Cmin, ss (ng/mL per mg dose) 1.71.5 ; Trough 1 (time 0) (ng/mL per mg dose) 3.62.9 ; Trough 2 (time 12) 2.62.6. 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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Podaci o prilogu
164-165.
2014.
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objavljeno
Podaci o matičnoj publikaciji
Basic & clinical pharmacology & toxicology
1742-7835
Podaci o skupu
17th World Congress of Basic and Clinical Pharmacology
poster
13.06.2014-18.06.2014
Cape Town, Južnoafrička Republika