| Abstract | Mikofenolna kiselina (MPA) pokazuje varijabilnu farmakokinetiku (PK). Metabolizira se enzimima UGT u MPA-glukuronid koji podliježe enterohepatičkoj recirkulaciji. U izlučivanje putem žuči i bubrega uključen je i protein multirezistencije 2 (MRP2) kodiran genom ABCC2. Ispitali smo PK MPA u stanju ravnoteže u ispitanika s bubrežnim presatkom u odnosu na genotip ABCC2 donora i primatelja, uz druge kliničke kovarijable uključujući komedikaciju s ciklosporinom ili takrolimusom. Bolesnici (n=68, muškarci=53%, dob 15-72 godine) su dobivali mikofenolat-natrij, (EC-MPS) (n= 45, 2x720 mg/dan) ili mikofenolat mofetil (MMF) (n=23, 2x500 do 2x1000 mg/dan) i svi su dobivali ciklosporin (n=43) ili takrolimus (n= 25) te kortikosteroide. Uzorak krvi se uzimao tijekom jednog intervala doziranja (12 sati) u 0, 0.5, 1, 2, 3, 8, 12 h nakon jutarnje doze. MPA je analizirana metodom HPLC. Genotipizacija ABCC2 -24C>T i 1249G>A je provedena metodom PCR u stvarnom vremenu. PK parametri (ln-transformirani) su analizirani prilagodbom generalnog linearnog modela s neovisnim parametrima za dob, spol, indeks tjelesne mase, liječenje (EC-MPS ili MMF), vrstu kalcineurinskog inhibitora te genotip donora i primatelja (-24C>T i 1249G>A). S obzirom na genotip donora ABCC2: alel -24T je neovisno povezan s nižimom Cmin (omjer geometrijskih sredina, GMR=0.61, 90% CI 0.40-0.92), nižom ostatnom koncentracijom Co (GMR=0.54, 0.35-0.83), nižom ostatnom koncentracijom C12 (GMR 0.61, 0.37-0.99) i većim oscilacijama koncentracija MPA (GMR=1.88, 1.09-3.23). S obzirom na genotip primatelja ABCC2: alel 1249A je neovisno povezan s nižom Cmin (GMR=0.55, 0.36-0.66), nižom ostatnom koncentracijom C12 (GMR=0.54, 0.32-0.90) i većim oscilacijama koncentracija MPA (GMR=1.85, 1.05-3.28). Pacijenti liječeni ciklosporinom i koji su bili nositelji alela ABCC2 1249A (niska aktivnost), imali su za 30 % niži AUC MPA u odnosu na pacijenate liječene s takrolimusom, a koji su imali genotip visoke aktivnosti, ABCC2 1249GG. Kombinacija ciklosporina i varijantnih alela ABCC2 (-24T, 1249A) bila je povezana s Cmax/AUC, povišenima za 60%, odnosno 52%. Zaključujemo da je farmakokinetika MPA pod značajnim utjecajem polimorfizama ABCC2 donora i primatelja te ciklosporina u istodobnoj terapiji što može biti klinički značajno. |
| Abstract (english) | Mycophenolic acid (MPA) displays variable pharmacokinetics (PK). It is metabolized by UGTs to MPA-glucuronide which is subject to enterohepatic recirculation. Biliary and kidney excretion involves multidrug resistant protein 2 (MRP2) coded by ABCC2. We assessed steady-state PK of MPA in renal allograft recipients in respect to donor and recipient ABCC2 genotypes, along with other clinical covariates including commedication with cyclosporine or tacrolimus. Patients (n=68, men=53%, age 15-72 years) were treated with mycophenolate sodium (EC-MPS) (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. MPA was analysed by HPLC method. Genotyping of -24C>T and 1249G>A was performed by Real-time PCR method. PK parameters (ln-transformed) were analysed by fitting generalized linear models with independents: age, sex, body mass index, treatment (EC-MPS or MMF), calcineurin inhibitor type, donor and recipient genotypes (-24C>T and 1249G>A). Regarding the donor ABCC2 genotypes: -24T allele was independently associated with lower Cmin (geometric mean ratio, GMR=0.61, 90% CI 0.40-0.92), lower trough Co (GMR=0.54, 0.35-0.83), lower trough C12 (GMR 0.61, 0.37-0.99) and greater MPA concentration oscillations (GMR=1.88, 1.09-3.23). Regarding the recipient genotypes: 1249A allele was independently associated with lower Cmin (GMR=0.55, 0.36-0.66), lower trough C12 (GMR=0.54, 0.32-0.90) and greater % swing (GMR=1.85, 1.05-3.28). Patients treated with cyclosporine and who were carriers of ABCC2 1249A (low activity) , had a 30% lower AUC MPA compared to the patients treated with tacrolimus and who had the high activity genotype, 1249GG. The combination of cyclosporine and variant alleles ABCC2 (-24T, 1249A) was associated with a Cmax / AUC, increased by 60 % and 52 %. In conclusion, the pharmacokinetics of MPA is significantly affected by the donor and recipient ABCC2 polymorphisms and cyclosporine in concomitant therapy, which could be clinically relevant.
The thesis is |
