Faktori od značaja za farmakokinetiku ciklosporina A kod dece sa transplantiranim bubregom
Important factors for pharmacokinetics of cyclosporine A in children with kidney transplant
Doktorand
Cvetković, Mirjana Z.Mentor
Kostić, MirjanaČlanovi komisije
Ležaić, VišnjaNaumović, Radomir
Živković, Maja
Metapodaci
Prikaz svih podataka o disertacijiSažetak
Transplantacija bubrega je najpoželjniji metod lečenja pedijatrijskih pacijenata sa
terminalnom bubrežnom insuficijencijom, a Ciklosporin A (CsA) je imunosupresivni
lek koji se koristi kod transplantiranih bolesnika u cilju prevencije odbacivanja kalema.
Različita ekspresija komponenata familije enzima CYP3A (prvenstveno CYP3A4 i
CYP3A5), POR enzima i P-glikoproteina može biti uzrok individualne varijabilnosti u
apsorpciji, metabolizmu i tkivnoj distribuciji CsA. Individualni odgovor na terapiju
može biti uslovljen prisustvom različitih alelnih varijanti (polimorfizama tipa zamene
jednog nukleotidnog ponovka , eng. single nucleotide polymorphisms-SNP) u genima
koji kodiraju navedene enzime i transporter. Takođe, biološko sazrevanje dečijeg
organizma doprinosi razlikama u farmakokinetici CsA u grupi pedijatrijskih pacijenata.
Ciljevi studije: 1. da se utvrdi frekvencija alela i genotipova polimorfizama u genima
za ABCB1 (rs1045642), CYP3A5 (rs776746), CYP3A4 (rs35599367) i POR
(rs105786...8) kod pedijatriskih pacijenata sa transplantiranim bubregom u Srbiji, 2. da se
ispita uticaj uzrasta pacijenta, kao nezavisnog faktora, na farmakokinetiku CsA tokom
prve godine nakon transplantacije, 3. da se ispita uticaj polimorfizama u genima za
ABCB1 (rs1045642), CYP3A5 (rs776746), CYP3A4 (rs35599367) i POR (rs1057868)
na farmakokinetiku CsA kod pedijatrijskih pacijenata sa transplantiranim bubregom u
Srbiji, tokom prve godine nakon transplantacije, 4. da se ispita uticaj polimorfizama u
genima za ABCB1 (rs1045642), CYP3A5 (rs776746), CYP3A4 (rs35599367) i POR
(rs1057868) u zavisnosti od uzrasta pacijenta, na farmakokinetiku CsA kod
pedijatrijskih pacijenata sa transplantiranim bubregom u Srbiji, tokom prve godine
nakon transplantacije.
Metodologija: Istraživanje je obavljeno na Univerzitetskoj dečjoj klinici, u Centru za
hemodijalizu i transplantaciju, jedinom mestu u Srbiji, gde se radi transplantacija
bubrega kod pedijatrisjkih pacijenata uz njihovo postransplantaciono praćenje. U studiju
je uključeno 47 pacijenata kojima je transplantiran bubreg u periodu od 2001-2015
godine. Pacijentima je nakon transplantacije uključen CsA u terapiju...
Kidney transplantation is the most desirable method for the treatment of children with
terminal renal insufficiency and Cyclosporine A (CsA) is a cornerstone of
immunosuppressive therapy used in transplanted patients, in order to prevent the
rejection of kidney. Different expression of components of the CYP3A enzyme family
(primarily CYP3A4 and CYP3A5), POR enzyme and of P-glycoprotein, may be the
cause of individual variability in absorption, metabolism and tissue distribution of CsA.
Individual response to therapy may be conditioned by the presence of various allelic
variants (single nucleotide polymorphisms-SNP) in genes encoding said enzymes and a
transporter. Also, biological maturation of child organism contributes to differences in
the pharmacokinetics of CsA in a group of pediatric patients.
Aim: 1.to determine the frequency of alleles and genotypes of polymorphisms in genes
for ABCB1 (rs1045642), CYP3A5 (rs776746), CYP3A4 (rs35599367) and POR
(rs1057868) in children with kidne...y transplants in Serbia; 2. to investigate the effect of
polymorphisms in the genes of ABCB1 (rs1045642), CYP3A5 (rs776746), CYP3A4
(rs35599367) and POR (rs1057868) on the pharmacokinetics of CsA in children with
kidney transplants in Serbia; 3. to consider the influence of child age as an independent
factor on the pharmacokinetics of CsA in children with kidney transplants in Serbia; 4.
to investigate the effect of polymorphisms in the genes of ABCB1 (rs1045642),
CYP3A5 (rs776746), CYP3A4 (rs35599367) and POR (rs1057868) on the age of the
patient, on the pharmacokinetics of CsA in children with kidney transplants in Serbia.
Methodology: The research was carried out at the University Children's Hospital, at the
Center for Hemodialysis and Transplantation, the only place in Serbia, where kidney
transplants are performed, in line with post-transplant monitoring. The study included
47 children who had a kidney transplant in the period of 2001-2015. Patients received
CsA in the after transplantation treatment. Regular controls were performed 1, 3, 6 and
12 months after the transplantation and whenever needed by the doctor's assessment...