Factors influencing concentration-to-dose ratio of lamotrigine in Thai patients

Abstract

Background Genetic variation is one of factors that contribute to the interindividual variability of pharmacokinetic. UGT1A4 is the major enzyme responsible for lamotrigine metabolism. Therefore, UGT1A4 polymorphisms could lead to the variability of glucuronidation enzyme activity and may contribute to the difference of lamotrigine pharmacokinetics among ethnicities. Objectives To investigate the effect of genetic (UGT1A4 polymorphisms) and non-genetic factors (age, gender, body weight, and co-medications) on lamotrigine concentration-to-dose ratio (LTG-CDR) in Thai patients. Methods A prospective analysis study in 73 patients from Prasat Neurological Institute, who had stable lamotrigine dose for at least 2 weeks. Lamotrigine plasma concentration was determined using HPLC method. Genotyping of UGT1A4 was carried out by Taqman allelic discrimination assays. ANOVA was used to compare LTG-CDR among groups of different polymorphism. Multiple regression analysis was performed to investigate an association of all factors and LTG-CDR. Results The allele frequency of UGT1A4 142 T>G in Thai patients was 27%. However, the variant of UGT1A4 70 C>T was not found. The LTG-CDR of patients having at least 1 variant allele (T/G or G/G) was significantly lower than patients having wild type allele (T/T) for patients using lamotrigine monotherapy or lamotrigine + enzyme inhibitor + enzyme inducers (p=0.019). The stepwise regression model showed that age, the use of enzyme inducers, and enzyme inhibitor influence LTG-CDR. This model could explain 20.40% of the variance of LTG-CDR.Conclusion UGT1A4 polymorphism may contribute to the variability of LTG-CDR in Thai population. However, after accounting for age and co-medications, the influence of UGT1A4 polymorphism was not found.