SYMPOSIA

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org
Poster Presentations
[PP-017] Ref. No: 312
Interethnic differences in UGT1A4 genetic polymorphisms in Mexican and
Spanish populations
Marisol López 1 , Pedro Dorado 2 , Alberto Ortega 1 , Eva Peñas Lledó 2 , Nancy Monroy 3 , Esther Machín 2 , María Elisa Alonso 3 , Adrián Llerena 2
1 Department of Biological Systems, Universidad Autónoma Metropolitana-Xochimilco, Mexico City, Mexico
2 CICAB Clinical Research Centre. Extremadura University Hospital and Medical School. Servicio Extremeño de Salud, Badajoz, Spain
3 Department of Neurogenetics and Molecular Biology, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico
E-mail: allerena@unex.es
Clinical treatment with antiepileptics exhibits large interpatient variability. The UDP-glucuronosyltransferase (UGT) 1A4 is an enzyme
responsible for the conjugation of glucuronic acid in diverse functional groups included in various antiepileptic drugs, such as lamotrigine
and phenytoin. Several genetic polymorphisms of UGT1A4 have been described in different populations; among them, two nonsynonymous
single nucleotide polymorphisms (SNPs) 70A>C (P24T; UGT1A4*2) and 142T>G (L48V; UGT1A4*3b), as well as a synonymous
variant SNP 471T>C (C157C; UGT1A4*1b). P24T and L48V polymorphisms reduce the glucuronidation activity on various substrates.
Recently, it has been shown that L48V polymorphism decreases the serum concentration of lamotrigine in patients on monotherapy or
polytherapy, resulting in clinical outcome variability.
The main goal of this study was to determine the allelic frequencies of UGT1A4*1b, UGT1A4*2 and UGT1A4*3b in a sample of Mexican
Mestizo (MM) and Spaniard (SP) healthy volunteers. UGT1A4 genotyping is clinically important in order to identify patients who may be
at an increased risk for failure of therapy and/or adverse effects to anticonvulsants such as phenytoin and lamotrigine.
In this study, the allelic frequencies of these three UGT1A4 variants were determined by combined methodology of RFLPs and RT-PCR in
MM and SP populations. The allelic frequencies of the three UGT1A4 polymorphisms analyzed showed interethnic differences between
MM and SP, that was statistically significant for UGT1A4*1b (0.17 and 0.08, respectively; p=0.002).
These data could help clinicians to improve clinical response during treatment with UGT1A4 antiepileptic drug substrates in these
populations.
Key words: Interethnic differences, UGT1A4, genetic polymorphism.
Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S131
[PP-018] Ref. No: 315
Influence of CYP2C9 genetic polymorphism on losartan oxidation in an
Ecuadorian population
Pedro Dorado, Eva Peñas Lledó, Esther Machín, Adrián Llerena, Enrique Terán, Leonardo Beltrán
CICAB Clinical Research Centre. Extremadura University Hospital and Medical School. Servicio Extremeño de Salud, Badajoz, Spain. Biomedical Centre, Central University
of Ecuador and Health Science College, Universidad San Francisco de Quito, Quito, Ecuador
E-mail: allerena@unex.es
Background: Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme catalyzing the metabolism of several important drugs. CYP2C9
metabolizes a number of therapeutically important drugs, including most nonsteroidal anti-inflammatory drugs, S-warfarin, phenytoin,
and losartan. CYP2C9 is also involved in the metabolism of several important psychoactive substances (tetrahydrocannabinol, fluoxetine,
amitriptyline, phenytoin, etc.). It has been reported that CYP2C9 activity is modulated by endogenous substrates such as adrenaline and
serotonin. The involvement of CYP2C9 in the metabolism of melatonin has also been suggested.
Losartan has recently been suggested as a selective probe for CYP2C9 metabolic activity.
Objective: The aim of the study was to determine the activity of CYP2C9, using losartan as a probe drug, in relation to CYP2C9 genotype
in healthy Ecuadorian subjects.
Methods: A single oral dose of 50 mg losartan was given to 194 Ecuadorian unrelated subjects. Concentrations of losartan and its
carboxylic acid metabolite, E3174, were analyzed by means of high-performance liquid chromatography in urine collected for 8 h. The
CYP2C9 genotypes were determined in 194 subjects using specific methods for CYP2C9*2 and CYP2C9*3.
Results: The frequencies of the allelic variants CYP2C9*2 and CYP2C9*3 were 0.054 and 0.015, respectively. The urinary losartan/E3174
ratio was significantly higher (p=0.027) in subjects with the CYP2C9*1/*3 genotype (mean±SD, 12.4±13.8; n=6) than in subjects with the
CYP2C9*1/*1 (4.9±7.0; n=167).
S131