Title Utjecaj genskoga polimorfizma enzima UGT1A4 i UGT2B7 te transportnih proteina ABCB1 i ABCG2 na koncentraciju lamotrigina u serumu Title (english) Influence of genetic polymorphisms of UGT1A4 and UGT2B7 enzymes and ABCB1 and ABCG2 transport proteins on lamotrigine serum concentrations Author Ivana Šušak Sporiš Mentor Nada Božina (mentor)Committee member Željka Petelin Gadže (predsjednik povjerenstva)Committee member Vladimir Trkulja (član povjerenstva)Committee member Zlatko Trkanjec (član povjerenstva)Granter University of Zagreb Defense date and country 2024-01-11, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 615 - Pharmacology. Therapeutics. Toxicology Abstract Uvod: Lamotrigin karakterizira značajna interindividualna varijabilnost farmakokinetičkih parametara te je posljedično tome prisutna varijabilnost u učinkovitosti i razvoju štetnih učinaka. Do sada nije razjašnjena uloga polimorfizama metaboličkih enzima UGT1A4 i UGT2B7 te transportnih proteina ABCB1 i ABCG2 na bioraspoloživost lamotrigina.
Svrha: Cilj ovog istraživanja bio je procijeniti razlikuju li se nositelji varijantnog alela UGT2B7 c.-161C>T (rs7668258), UGT1A4*3 c.142T>G (rs2011425), ABCB1 c.1236C>T (rs1128503) i ABCG2 c.421C>A (rs2231142) od odgovarajućih kontrola divljeg tipa (engl. wild type, wt) s obzirom na izloženost lamotriginu.
Metode: U istraživanje su uključeni adolescenti i odrasle osobe s epilepsijom koji su uzimali monoterapiju lamotrigina ili politerapiju lamotrigina i valproata te su bili podvrgnuti rutinskom terapijskom praćenju lijeka. Ispitanici su inače bili zdravi i nisu uzimali druge lijekove koji bi mogli stupiti u interakciju s lamotriginom i valproatom. Uključeni ispitanici genotipizirani su za UGT2B7 c.-161C>T, UGT1A4*3 c.142T>G, ABCB1 c.1236C>T i ABCG2 c.421C>A. Heterozigotni i varijantni homozigotni ispitanici uspoređivani su sa svojim kontrolama divljeg tipa za ostatne koncentracije lamotrigina (standardizirane po dozi)
s prilagodbom prema dobi, spolu, tjelesnoj težini, ostalim ispitivanim polimorfizmima i razinama izloženosti valproatu. Za „ujednačavanje“ vrijednosti kovarijata korišteno je uravnoteživanje entropije.
Rezultati: Uključena je ukupno 471 osoba s epilepsijom, od čega je njih 328 (69.6%) bilo na monoterapiji, a 143 su bili na politerapiji lamotrigina i valproata. Rezultati su pokazali da su nositelji varijantnog alela ABCG2 c.421C>A imali koncentracije lamotrigina niže za 25% u odnosu na kontrole divljeg tipa u slučaju da su ispitanici bili na monoterapiji lamotriginom (valproat 0) ili na kombiniranoj terapiji lamotrigina i valproata (LAM + VAL) ukoliko su koncantracije valproata bile ispod razine kvantifikacije (engl. below the lower limit of quantification, BLOQ). Nije dokazana razlika u koncentracijama lamotrigina između nositelja
varijatnog alela i nositelja divljeg tipa kod ispitanika na kombiniranoj terapiji LAM + VAL ukoliko je koncentracija valproata bila <364 μmol/L [„nizak valproat“ (vrijednosti GMR oko 1.0)], dok su nositelji varijantnog alela imali 30% više koncentracije lamotrigina ukoliko je valproat bio >364 μmol/L [„visok valproat“ - unutar terapijskog raspona ili više (GMR =1.37, 1.03-1.82 frekvencionistička procjena, 1.31, 0.93-1.84, Bayes procjena)]. Nadalje, procijenjen je efekt valproata na dvije razine ABCG2 c.421C>A polimorfizma, tj. u kontrola „divljeg tipa“ i nositelja varijantnog alela. Efekt „visokog valproata“ bio je izraženiji u nositelja varijantnog alela nego u homozigota divljeg tipa (omjer GMR 1.80), kao i efekt „niskog valproata“ (omjer GMR 1.50). Ostatne koncentracije lamotrigina (standardizirane prema dozi) bile su podjednake u nositelja varijantnih alela i kontrola divljeg tipa za UGT2B7 c.-161C>T, UGT1A4*3 c.142T>G i ABCB1 c.1236C>T.
Zaključak: Rezultati istraživanja sugeriraju da polimorfizam ABCG2 c.421C>A moderira učinak valproata na izloženost lamotriginu, dok polimorfizmi UGT2B7 c.-161C>T, UGT1A4*3 c.142T>G i ABCB1 c.1236C>T nemaju relevatnog učinka na bioraspoloživost lamotrigina u osoba s epilepsijom.
Abstract (english) Introduction: Lamotrigine is characterized by significant interindividual variability in pharmacokinetic parameters and, consequently, there is variability in efficacy and the risk for adverse reactions. The role of polymorphisms of UGT1A4 and UGT2B7 metabolic enzymes as well as ABCB1 and ABCG2 transport proteins on the lamotrigine bioavailability has not
yet been clarified.
Purpose: To estimate whether epilepsy patients with variant UGT2B7 c.-161C>T (rs7668258), UGT1A4*3 c.142T>G (rs2011425), ABCB1 c.1236C>T (rs1128503) and ABCG2 c.421C>A (rs2231142) alleles differ from their wild-type (wt) peers in exposure to lamotrigine.
Methods: Consecutive adults on lamotrigine monotherapy or lamotrigine and valproate cotreatment undergoing routine therapeutic drug monitoring, otherwise generally healthy and free of interacting drugs, were genotyped for UGT2B7 -161C>, UGT1A4*3 c.142T>G, ABCB1 c.1236C>T (rs1128503) and ABCG2 c.421C>A. Heterozygous and variant homozygous subjects were compared to their wt controls for dose-adjusted lamotrigine troughs with adjustment for age, sex, body weight, other evaluated polymorphisms, and level of exposure to valproate using covariate entropy balancing.
Results: Of the 471 included patients, 328 (69.6%) were on monotherapy and 143 were cotreated with valproate. The results showed that c.421C>A variant allele carriers had by 25% lower lamotrigine concentrations compared to wild-type controls if the subjects were on lamotrigine monotherapy or lamotrigine and valproate (LAM + VAL) polytherapy if valproate troughs were below the lower limit of quantification (BLOQ). Variant c.421C>A allele had no obvious effect on lamotrigine troughs if valproate concentrations were <364 μmol/L [low valproate (GMR 1.0)], and increased lamotrigine troughs by 30% if valproate > 364 μmol/L [target/high valproate (GMR =1.37, 1.03-1.82 frequentist; 1.31, 0.93-1.84, Bayesian)]. Furthermore, we evaluated the effect of valproate on two levels of the ABCG2 c.421C>A polymorphism ("wild type" controls and variant allele carriers). The "high valproate" effect was more pronounced in the variant allele carriers than in the wild-type homozygotes (GMR ratio 1.80), as was the "low valproate" effect (GMR ratio 1.50). Dose-adjusted lamotrigine troughs in UGT2B7 c.-161C>T, UGT1A4*3 c.142T>G and ABCB1 c.1236C>T variant allele carriers were closely similar to those in their wt controls.
Conclusion: Data suggests that ABCG2 c.421C>A polymorphism moderates the effect of valproate on exposure to lamotrigine, while dose-adjusted lamotrigine troughs in epilepsy patients with variant UGT2B7 c.-161C>T, UGT1A4*3 c.142T>G or ABCB1 c.1236C>T alleles are equivalent to those in their respective wt peers.
Keywords
lamotrigin
valproat
genski polimorfizam
UGT2B7 c.-161C>T
UGT1A4*3 c.142T>G
ABCB1 c.1236C>T
ABCG2 c.421C>A
Keywords (english)
lamotrigine
valproate
genetic poliymorphism
UGT2B7 c.-161C>T
UGT1A4*3 c.142T>G
ABCB1 c.1236C>T
ABCG2 c.421C>A
Language croatian URN:NBN urn:nbn:hr:105:501896 Study programme Title: Biomedicine and Health Sciences Type of resource Text Extent 120 str. File origin Born digital Access conditions Open access Terms of use Created on 2024-01-18 09:07:21
