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doctoral thesis
Učinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom
Zagreb: University of Zagreb, Faculty of Pharmacy and Biochemistry, 2023. urn:nbn:hr:163:870924
Borić Bilušić, Ana
University of Zagreb
Faculty of Pharmacy and Biochemistry
Department of medical biochemistry and haematology

Institutional repository: Repository of Faculty of Pharmacy and Biochemistry University of Zagreb

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Borić Bilušić, A. (2023). Učinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom (Doctoral thesis). Zagreb: University of Zagreb, Faculty of Pharmacy and Biochemistry. Retrieved from https://urn.nsk.hr/urn:nbn:hr:163:870924

Borić Bilušić, Ana. "Učinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom." Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, 2023. https://urn.nsk.hr/urn:nbn:hr:163:870924

Borić Bilušić, Ana. "Učinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom." Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, 2023. https://urn.nsk.hr/urn:nbn:hr:163:870924

Borić Bilušić, A. (2023). 'Učinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom', Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, accessed 29 April 2024, https://urn.nsk.hr/urn:nbn:hr:163:870924

Borić Bilušić A. Učinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom [Doctoral thesis]. Zagreb: University of Zagreb, Faculty of Pharmacy and Biochemistry; 2023 [cited 2024 April 29] Available at: https://urn.nsk.hr/urn:nbn:hr:163:870924

A. Borić Bilušić, "Učinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom", Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, Zagreb, 2023. Available at: https://urn.nsk.hr/urn:nbn:hr:163:870924

Metadata
TitleUčinak farmakogenetičkih varijacija UGT1A9, CYP3A4 i CYP3A5 na farmakokinetiku mikofenolne kiseline primijenjene s ciklosporinom ili takrolimusom u bolesnika s presađenim bubregom
Title (english)Effect of pharmacogenetic variants of the UGT1A9, CYP3A4 and CYP3A5 on pharmacokinetic of mycophenolic acid administered in commedication with cyclosporine or tacrolimus in renal transplant recipients
AuthorAna Borić Bilušić
MentorKarmela Barišić (mentor)
Committee memberMila Lovrić (predsjednik povjerenstva)
Committee memberMario Laganović (član povjerenstva)
Committee memberJelena Osmanović (član povjerenstva)
GranterUniversity of Zagreb
Faculty of Pharmacy and Biochemistry
(Department of medical biochemistry and haematology)
Zagreb
Defense date and country2023-12-22, Croatia
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Pharmacy
Medical Biochemistry
Universal decimal classification
(UDC)		615 - Pharmacology. Therapeutics. Toxicology
Abstract
Cilj je ovoga istraživanja ispitati utjecaj polimorfizama metaboličkih enzima UGT i CYP te ABC transportera na bioraspoloživost mikofenolne kiseline (MPA) u stanju dinamičke ravnoteže primijenjene u kombinaciji s ciklosporinom (CsA) ili takrolimusom (TAC) kod bolesnika s transplantiranim bubregom. Analizirana je povezanost genske varijabilnosti metaboličkog enzima UGT1A9 te membranskog prijenosnika ABCG2 s bioraspoloživosti MPA-a. Dodatno je provedena i analiza utjecaja genske varijabilnosti metaboličkih enzima CYP3A4 i CYP3A5 s koncentracijama CsA-a i TAC-a te su procijenjeni dometi interakcije MPA-a s CsA-om i TAC-om u odnosu na ispitane varijante gena ABCG2 u bolesnika s transplantiranim bubregom. U istraživanje je bilo uključeno je 68 bolesnika (n=68, muškarci=35, dob 16-71) na standardnom imunosupresivnom protokolu koji uključuje MPA, CsA ili TAC te kortikosteroide. Uzorci krvi uzeti su tjedan dana nakon početnoga doziranja. Uzorak krvi za određivanje ostatnih koncentracija MPA, CsA i TAC-a, uzet je u 8h ujutro prije jutarnje doze lijeka nakon čega je uslijedila standardna jutarnja doza. Tijekom 12-satnoga intervala doziranja za MPA je uzeto 6 uzoraka krvi za određivanje koncentracije MPA. MPA je analizirana HPLC metodom, a genotipizacija polimorfizama UGT1A9 -2152C>T i -275 T>A, CYP3A4*22, CYP3A5*3, ABCG2 c.421C>A, ABCC2 24 C>T i 1249 G>A, ABCB1 2677G>T/A, 3435C>T, 1236C>T, SLCO1B1 c.521T>C je provedena metodom lančane reakcije polimeraze u stvarnom vremenu (qPCR). Bolesnici homozigoti divljega tipa i nositelji varijantnoga alela ABCG2 c.421C>A ujednačeni su metodom egzaktnoga uparivanja u kombinaciji s optimalnim potpunim uparivanjem u odnosu na demografske, biofarmaceutske i genetičke varijable te je procijenjen učinak varijantnoga alela (frequentist, Bayes) usporedbom omjera geometrijskih srednjih vrijednosti (GMR) farmakokinetičkih parametara MPA ujednačenih prema dozi u stanju dinamičke ravnoteže. Dobiveni rezultati ukazuju na značajnu povezanost varijantnoga alela ABCG2 c.421C>A i farmakokinetike MPA-a. Kod stabilnih bolesnika s transplantiranim bubregom koji su ujedno i nositelji varijantnoga alela ABCG2 c.421C>A, rezultati ukazuju na povećanu bioraspoloživost MPA (AUCτ,ss ≈ 40 %) u skladu s proporcionalno smanjenim klirensom (CLT/F,ss ≈ 30 %). Dodatno je uočena značajna uloga polimorfizma ABCG2 c.421 C>A u moduliranju interakcije CsA-a i TAC-a s MPA-a. Rezultati upućuju na znatno izraženiji učinak varijantnoga alela ABCG2 c.421C>A u skupini bolesnika na terapiji TAC-om kod kojih je zabilježena dva puta veća bioraspoloživost MPA, manji klirens i manja brzina apsorpcije u odnosu na skupinu bolesnika na terapiji CsA-om. Rezultati nisu pokazali utjecaj ispitivanih polimorfizama metaboličkog enzima UGT1A9 na koncentracije MPA-a. Također nije zabilježen ni značajan utjecaj polimorfizama enzima CYP3A4 i CYP3A5 na koncentracije CsA-a i TAC-a, moguće zbog malog broja bolesnika nositelja varijantnih alela.
Abstract (english)
The aim of this research was to analyse the influence of metabolic enzymes UGTs, CYPs and ABCs transporter polymorphism on steady-state mycophenolic acid (MPA) exposure applied in commedication with cyclosporine (CsA) or tacrolimus (TAC) in renal transplant recipients. The association between the genetic variability of the metabolic enzyme UGT1A9 and the membrane transporter ABCG2 and the MPA bioavailability was analysed. In addition, an analysis of the influence of the genetic variability of the metabolic enzymes CYP3A4 and CYP3A5 on the concentrations of CsA and TAC was performed. The range of MPA interaction with CsA and TAC in relation to the tested variants of the ABCG2 gene in kidney transplant patients was also evaluated. The study included 68 patients (n=68, men=35, age 16-71) on standard immunosuppresant protocols including MPA, CsA or TAc and glucocorticoids. Blood samples were taken after completion of the initial week of treatement, at 8.00 a.m. before the next dose for quantification of MPA, CsA or TAC trough concentrations followed by the standard morning dose. During the 12-hour dosing interval for MPA, six blood samples were taken to determine MPA concentration. Total plasma MPA was determined by HPLC method, genotyping of polymorphisms UGT1A9 -2152C>T i -275 T>A, CYP3A4*22, CYP3A5*3, ABCG2 c.421C>A, ABCC2 24 C>T i 1249 G>A, ABCB1 2677G>T/A, 3435C>T, 1236C>T, SLCO1B1c.521T>C was performed by real-time polymerase chain reaction (qPCR). Homozygous wild type patients and ABCG2 c.421C>A variant allele carriers were matched in combined exacted and optimal full matching with respect to demographic, biopharmaceutic and genetic variables. Variant allele effect was assessed by comparing the ratio of geometric means (GMR) of dose adjusted steady state MPA pharmacokinetics estimates (frequentist and Bayes). Results indicate significant association between ABCG2 c.421C>A variant allele and MPA pharmacokinetics. In stable renal transplant recipients ABCG2 c.421C>A variant allele carriers results showed an increased MPA bioavailability (AUCτ,ss ≈ 40 %) in accordance with proportionally reduced clearance (CLT/F,ss ≈ 30 %) Additionally, significant role of the ABCG2 c.421C>A polymorphism in modulating the interaction of CsA and TAC with MPA was observed. Results imply a significantly more pronounced effect of the ABCG2 c.421C>A variant allele in patients on TAC therapy. Two times higer MPA bioavailability, lower clearance and slower absorption rate were recorded compared to the patients on CsA therapy. Results showed no influence of the tested polymorphisms of the metabolic enzyme UGT1A9 on MPA concentrations. Also, there was no overall effect of CYP3A4 and CYP3A5 enzyme polymorphisms on CsA and TAC concentrations, possibly due to small number of patients carrying variant alleles.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:163:870924
Promotion2023
Study programmeTitle: Pharmacy and biochemistry
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor znanosti (doktor znanosti)
Type of resourceText
File originBorn digital
Access conditionsOpen access
Terms of useLicence In copyright icon
Created on2024-01-31 12:57:00