Naslov
LAMOTRIGINE AND VALPROATE DRUG INTERACTIONS - THE ROLE OF PHARMACOGENOMICS

Autori
Klarica Domjanović, Iva ; Lovrić, Mila ; Petelin Gadže, Željka ; Ganoci, Lana ; Trkulja, Vladimir ; Božina, Nada

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Abstract Book of the 14th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology / - : IATDMCT, 2017 / - , 2017

Skup
15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology

Mjesto i datum
Kyoto, Japan, 24.09.2017. - 27.09.2017

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
lamotrigine ; valproate ; UGT enzymes ; ABCG2 ; genes polymorphisms

Sažetak
Background For the treatment of epilepsy anticonvulsants are often used as polytherapy. UDP-glucuronosyltransferase enzymes (UGTs) and some ABC transporters are involved in lamotrigine and valproic acid glucuronidation and transport, and these drugs are commonly administered in combination. The aim of the proposed research was to investigate the role of UGTs and ABCs transporter polymorphisms in interindividual variability of lamotrigine and valproate bioavailability. Methods 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 was performed by real time PCR method, using TaqMan assays. Results 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 and UGT1A4 70 C>A on either lamotrigine or valproate trough or trough/dose corrected concentrations. ABCB1 1236C>T genotypes also has no effect on lamotrigine and valproate concentrations. ABCG2 421C>A genotypes has no overall effect on either lamotrigine (adjusted GMR 1.12, p=0.285) or valproate trough concentrations (adjusted GMR 1.17, p=0.370), 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 ; GMR=0.80, p=0.085) indicating a significant (p=0.004) two-fold difference in A-allele effect between treatment subsets. Conclusions Our study did not confirm influence of UGT2B7, UGT1A4 and ABCB1 gene polymorphisms on lamotrigine trough plasma concentrations. 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). The role of ABCG2 genotype still needs to be confirmed in a larger polytherapy group.

Izvorni jezik
Engleski

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