The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy
Introduction
Genetic differences of enzymes which are involved in the metabolism of drugs are considered to be directly correlated with necessary dose adjustments. The reaction velocity of the metabolic enzymes coded by genetic polymorphisms can affect serum concentrations of drugs, which may cause changes in the effectiveness of the drugs or reveal adverse reactions and toxicity. Identification of genetic markers was reported to be important for developing safer drugs and improving personalized therapy (Franciotta et al., 2009).
Lamotrigine (LTG), which has a widespread use in the treatment of partial and generalized epilepsy seizures as well as Lennox Gestaut syndrome (Stefan and Feuerstein, 2007), is metabolized by glucuronidation conjugation by UDP-glucuronosyl transferase (UGT) enzymes (70%), present in hepatic microsomal fractions (Parsons et al., 1995, Bialer, 2005). The main metabolite of LTG is 2-N-glucuronide with a 75–90% found in the urine after a single oral dose of LTG (Londero and Greco, 1997). One of the members of the UGT1A gene family, the UGT1A4 enzyme, is mostly responsible not only for the metabolism of LTG (Hiller et al., 1999) but it also acts in the glucuronidation of substrates such as amitriptiline, imipiramine (Green and Tephly, 1996), clozapine (Mori et al., 2005), nicotine (Tricker, 2003), tamoxifene (Sun et al., 2006) and trans-androsterone (Ehmer et al., 2004).
Although LTG does not have any effect on the metabolism of other antiepileptic drugs (AEDs), the serum concentration of LTG has been shown to increase with valproic acid (VPA) (Yau et al., 1992, Yuen et al., 1992, Perruca, 1999, Bialer et al., 2007) or decrease with hepatic enzyme inducing drugs such as phenytoin, carbamazepine, phenobarbital or oral contraceptive agents (Garnett, 2002, Patsalos and Perucca, 2003, Sabers et al., 2003, Patsalos, 2005, Bialer et al., 2007, Öhman et al., 2008) as well as during pregnancy (Tomson et al., 1997, Franco et al., 2008) and with smoking (Reinsberger et al., 2008). A large inter-patient variability in the serum concentration of LTG was reported by Patsalos (1999) and Milovanovic and Jankovic (2009) for the optimum response. Additionally usefulness of therapeutic drug monitoring for LTG was reported due to the pharmacokinetic variability (Johannessen and Tomson, 2006).
Genetic polymorphisms of UGT enzymes have toxicological, pharmacological and physiological importance (Miners et al., 2002). Functional genetic polymorphisms of the UGT1A4 enzyme were firstly investigated by Ehmer et al. (2004). A proline to threonine amino acid change (P24T) was detected at codon 24 by a cytosine (C) to adenine (A) transversion at 70. nucleotide and a leucine to valine amino acid change (L48V) was determined at codon 48 by a threonine (T) to guanine (G) transversion at 142. nucleotide. Not only the frequencies but also the glucuronidation activities of P24T and L48V polymorphisms found in the first exon of the UGT1A4 gene have shown differences (Ehmer et al., 2004, Mori et al., 2005). These studies have pointed out the variation in the activity of the polymorphic UGT1A4 enzyme due to substrate specificity.
The aim of this study was to investigate: (1) P24T and L48V single nucleotide polymorphisms (SNP) of the UGT1A4 enzyme in a Turkish population of patients with epilepsy and (2) the functional effect of P24T or L48V variant UGT1A4 enzymes on the serum LTG concentration in monotherapy or polytherapy patients.
Section snippets
Methods
Patients with partial or generalized epileptic seizures from the epilepsy outpatient clinic of the Istanbul University, Cerrahpaşa Medical Faculty, Department of Neurology, between 18 and 50 years old and had been on LTG mono or polytherapy with other antiepileptics were included in this study. Patients needed to be on LTG treatment for at least two weeks so that they were in a steady state of drug levels. Of the 131 Turkish patients, 73 were women and 58 were men. The demographic
Results
Of the 131 DNA samples, 129 of them could be analyzed for the two polymorphisms. According to the genotype results, 5 patients were found to be heterozygous for the P24T polymorphism and 29 patients for the L48V polymorphism. Only 2 patients were detected homozygous for the L48V polymorphism and none of them were positive for the homozygous P24T polymorphism (Table 2).
The most frequent genotype was detected for the wild type alleles (72.09%, UGT1A4C/T or UGT1A424Pro/48Leu) (Table 3). The
Discussion
In the present study the frequency of the L48V and P24T polymorphisms and the functional effect of the L48V polymorphism of the UGT1A4 enzyme on the serum LTG level have been investigated in a Turkish population of patients with epilepsy.
According to our results, presence of the L48V polymorphism in a high percent of patients (22.4%) allowed us to define the functional effect of this polymorphism clearly. The L48V polymorphism was found to decrease the level of the serum concentration of LTG.
Disclosures
None of the authors has any conflict of interest to disclose.
Acknowledgements
This study was supported by the Marmara University Scientific Research Committee (SAG-C-TUP-061207-0226 and SAG-A-030408-0071). We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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