Author(s): Chun-Lai Ma aff1 , Xun-Yi Wu aff2 , Zheng Jiao aff1 , Zhen Hong aff2 , Zhi-Yuan Wu aff3 , Ming-Kang Zhong [*] aff1
ABCC2 ; epilepsy; genetic polymorphisms; oxcarbazepine; SCN1A ; SCN2A ; UGT2B7
The second-generation antiepileptic drug (AED) oxcarbazepine (Trileptal ® ; OXC) is a 10-keto analog of carbamazepine (CBZ) and used in both monotherapy and adjunctive therapy for the treatment of partial seizures with and without secondary generalizations. Although the mechanism of action, spectrum of activity and efficacy of oxcarbazepine (OXC) are comparable to those of CBZ, their pharmacokinetic and pharmacodynamic properties are different [1 ]. In clinical practice, significant interindividual variability in optimal OXC dose has been observed in epileptic patients taking OXC. Genetic variation may be an important factor contributing to variability in clinical pharmacokinetics and the drug requirements of individual patients [ 2 ].
When OXC is absorbed from the gastrointestinal tract, it is almost immediately reduced by cytosolic arylketone reductase to 10,11-dihydro-10-hydroxy-carbazepine (the monohydroxy derivative [MHD]), which is the main pharmacologically active metabolite [3 ]. The majority of the dose administered OXC is excreted by the kidneys as the inactive glucuronide conjugates of MHD (49%) and OXC (9%) and unchanged MHD (27%) by microsomal UDP-glucuronosyltransferases (UGTs), which are only weakly inducible [3 ]. UGT2B7 genetic polymorphisms underlie the variability in glucuronic acid metabolism among individuals [4 ]. The common variants in the UGT2B7 coding region, UGT2B7 211G[greater than]T and 802T[greater than]C, have been assessed in previous studies [5 ]. The allele frequency of the nonsynonymous polymorphism UGT2B7 802T[greater than]C (rs7439366) in the Chinese population is 32.8% [ 6 ]; this polymorphism causes a histidine-to-tyrosine substitution at position 268 of the protein [5 ]. The effects of these SNPs on glucuronidation remain unclear. The clinical effects of UGT2B7 genetic variants on OXC maintenance doses and concentrations have not yet been studied.
MDR1 (also known as P-gp, encoded by the ABCB1 gene) and MRPs (encoded by the ABCC genes), are important for the transport of AEDs across the blood-brain barrier [7,8 ]. In vitro transport studies have shown that all CBZ analogs and metabolites are active substrates of ABC transporters [9-11 ]. Reports of the genetic effects of ABCB1 polymorphisms on AED responses have been inconsistent. Meta-analyses have failed to observe an association between the ABCB1 C3435T polymorphism and drug resistance [12-14 ]. Therefore, ABCB1 polymorphisms most likely have low functional impacts. Recently emerging evidence has suggested that MRP2, which is encoded by the ABCC2 gene, may be associated with an altered response to AEDs; however, further studies are required to elucidate this association. ABCC2 c.-24C[greater than]T (promoter), c.1249G[greater than]A (exon 10) or rs2273697 (V417I) and the silent locus c.3972C[greater than]T (exon 28) or rs3740066 (I1324I) are common variants of the ABCC2 gene. Kim et al . have found that CBZ was a substrate of MRP2, and that the ABCC2 c.1249G[greater than]A variant was associated with neurological adverse reactions to CBZ in Korean epileptic patients [15 ]. Moreover the responses to AEDs have also been reported in association with the variants...