Utjecaj polimorfizama gena za uridin-difosfo-glukuronil transferazu na interakcije lamotrigina i valproata

doctoral thesis

• Title (english): Influence of uridine diphosphate glucuronosyltransferase gene polymorphisms on lamotrigine and valproate drug interactions
• Author: Iva Klarica Domjanović https://orcid.org/0000-0001-5488-5893
• Mentor: Mila Lovrić (mentor); MBZ: 245886
• Committee member: Nada Božina (predsjednik povjerenstva)
• Committee member: Ana Galov (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2018, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 577 - Biochemistry. Molecular biology. Biophysics

Abstract

Cilj ovog istraživanja bio je ispitati ulogu polimorfizama nekih enzima UGT i CYP te transportera ABC u interindividualnoj varijabilnosti bioraspoloživosti lamotrigina i valproata. U ključeno j e 205 pacijenata s dijagnosticiranom epilepsijom, podijeljenih u skupinu na monoterapiji lamotriginom (n=131) te skupinu na terapiji lamotriginom i valproatom (n=74). Koncentracija lamotrigina u serumu određena je metodom HPLC, dok je za k oncentraciju valproične kiseline primijenjena enzim-imunokemijska metoda. Genotipizacija UGT2B7 -161C>T, UGT1A4 142T>G, UGT1A4 70C>A, ABCB1 1236C>T, ABCG2 421C>A, je provedena metodom PCR u stvarnom vremenu koristeći testove TaqMan . Koncentracije lamotrigina, prilagođene prema dobi, spolu, indeku tjelesne mase, bile su oko 2,4 puta veće u pacijenata na politerapiji s valproatom. Nije dokazan ukupan učinak varijantnih alela UGT2B7 -161C>T, UGT1A4 142T>G i UGT1A4 70 C>A, ABCB1 1236C>T, CYP2C9*2, CYP2C9*3, CYP2C19*2 i CYP2C19*17 na koncentracije lamotrigina i vaproata. Uočena je značajna interakcija između alela ABCG2 421A u pacijenata na konkomitantnoj terapiji s lamotriginom i valproatom. Alel ABCG2 421A (vs. CC) povezan je sa 61% većom koncentracijom lamotrigina (P=0,019), dok je u pacijenata na monoterapiji lamotriginom alel 421A povezan s nešto manjom koncentracijom (vs. CC, P=0,085) ukazujući na značajnu razliku učinka alela ABCG2 421A ovisnu o primjenjenom lijeku (P=0,004). Koncentracije lamotrigina su značajno više u pacijenata na konkomitantnoj primjeni valproata bez obzira na genotip ABCG2 421C>A. Međutim taj utjecaj je dva puta veći u pacijenata nositelja alela ABCG2 421A (GMR=4,29) u odnosu na pacijente s genotipom 421CC (GMR=2,15).

Abstract (english)

The aim of the proposed research was to investigate the role of UGTs,CYPs and ABCs transporter polymorphisms in interindividual variability of lamotrigine and valproate bioavailability. A total of 205 patients were enrolled, 131 treated with lamotrigine alone and 74 treated with lamotrigine and valproate. Determination of drug concentrations was performed by HPLC with diode array detector for lamotrigine and by immunoassay method for valproate. Genotyping of UGT2B7 -161C>T, UGT1A4 142T>G, UGT1A4 70C>A, ABCB1 1236C>T, ABCG2 421C>A, CYP2C9*2, CYP2C9*3, CYP2C19*2 i CYP2C19*17 was performed by real time PCR method, using TaqMan assays. Lamotrigine trough concentrations, adjusted for age, sex, body mass index, dose, were around 2.4-fold higher in patients co-treated with valproate. There was no overall effect of variant allele of UGT2B7 -161C>T, UGT1A4 142T>G, UGT1A4 70 C>A, ABCB1 1236C>T, CYP2C9*2, CYP2C9*3, CYP2C19*2 i CYP2C19*17 either on lamotrigine or valproate trough or trough/dose corrected concentrations. But there appeared a significant interaction between A-allele carriage in lamotrigine-valproate-treated subjects. ABCG2 421A-allele carriage (vs. CC) was associated with 61% higher lamotrigine trough (P=0.019), whereas in lamotrigine-only-treated subjects, A-allele carriage was associated with somewhat lower trough (vs. CC p=0.085) indicating a significant (P=0.004) two-fold difference in A-allele effect between treatment subsets. Valproate was associated with significantly higher lamotrigine troughs regardless of the
ABCG2 genotype, but the effect appeared two-fold higher in ABCG2 421 A-allele carriers (GMR 4.29) than in 421CC-subjects (GMR 2.15).

• Keywords: lamotrigin; valproat; UGT; CYP; ABCG2; ABCB1; interakcija
• Keywords (english): lamotrigine; valproate; UGT; CYP; ABCG2; ABCB1; interaction
• Language: croatian
• URN:NBN: urn:nbn:hr:217:033078
• Study programme: Title: Biology; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2018-06-13 11:30:17