UGT2B7_−161C>T Polymorphism Is Associated With Lamotrigine Concentration-to-Dose Ratio in a Multivariate Study

Abstract

Lamotrigine (LTG) is metabolized by UGT1A4 but UGT2B7 also contributes to its glucuronidation. The aim of this study was to determine whether UGT2B7_- 161C>T and UGT2B7_372A>G polymorphisms contribute to the intersubject variability in LTG concentration-to-dose ratio (LTG-CDR) in epileptic patients. Fifty-three white epileptic patients attending the Neuropediatric and Neurology Services at the Marqués de Valdecilla University Hospital, in whom LTG serum concentration was to be measured for pharmacokinetic monitoring, were selected according to predefined criteria for LTG-CDR evaluation. All patients had at least one steady-state LTG serum concentration obtained before the first dose in the morning. Patients were classified in 3 groups of comedication: (1) LTG in combination with metabolism-inducer anticonvulsants (n = 22), (2) LTG in combination with valproate (n = 13), and (3) LTG as monotherapy (n = 16) or in combination with valproate and inducers (n = 2). Genotypes were determined by Applied Biosystems Genotyping Assays with TaqMan probes. A significant association was found between LTG-CDR and UGT2B7_-161C>T polymorphism (P = 0.021) when patient age and concomitant antiepileptic drugs were taken into account. Comedication explained 70% of the LTG-CDR variability, patient age 24%, and UGT2B7_-161C>T 12%. In contrast, a significant association between LTG-CDR and this polymorphism was not found in the bivariate study when age and comedication groups were not considered. A significant association between UGT2B7_372A>G and LTG-CDR was not found in the bivariate or the multivariate studies. UGT2B7_-161C>T polymorphism is significantly associated with LTG-CDR when comedication with other antiepileptic drugs and patient age are taken into account in a multivariate analysis.

Rash and multiorgan dysfunction following lamotrigine: could genetic be involved?

“…The UGT2B7-161C[T is a promoter polymorphism that may change the level of transcription of the enzyme [16,27]. However, our patient was homozygous for UGT2B7-161C allele and, reportedly, patients carrying this genotype would require a higher LTG dose than those carrying the CT or TT genotypes [16].…”

“…In one study, the 372A allele was found to be associated with an increased morphine glucuronidation activity [16,26] and, conceivably, the presence of the mutant allele G in our patient might be compatible with a lower activity of the enzyme.…”

“…However, our patient was homozygous for UGT2B7-161C allele and, reportedly, patients carrying this genotype would require a higher LTG dose than those carrying the CT or TT genotypes [16].…”

“…Moreover, it been suggested that, beside other factors (e.g., age, concurrent disease, body size, co-medications, pregnancy status, ethnicity), also UGT1A4, UGT2B7 and ABCB1 variants may also influence the pharmacokinetics of LTG and, consequently, explain its inter-individual variability [15][16][17].…”

“…Several polymorphisms have been detected within the UGT2B7 gene, and they have been associated to changes in glucuronidation activities. The two most common are UGT2B7 161C[T (rs#: 7668258) and 372A[G (rs#: 7662029), with allelic frequencies in Caucasians of 49-56 and 3-13 %, respectively [15,16,22,[24][25][26].…”