1 Introduction
Carbamazepine (CBZ), prescribed as a first-line treatment for focal or generalized tonic-clonic epileptic seizures, is diverse from individuals among CBZ daily maintenance doses, plasma concentrations, and treatment efficacy [1]. The difference of pharmacodynamics and pharmacokinetics of CBZ varied from environmental factors co-medication to genetic variation [2], among which genetic variation of drug-resistance and drug-metabolizing enzymes were found play critical roles in CBZ therapy for epileptics [3, 4].
CBZ, catalyzed by cytochrome P450 3A4 (CYP3A4) , can generate a bioactive metabolite carbamazepine-10,11-epoxide (CBZE) of which possess a strongly antiepileptic activity [5]. Subsequently, CBZE inactivated to carbamazepine-10,11-transdihydrodiol (CBZD) by microsomal epoxide hydrolase which is encoded by microsomal epoxide hydrolase (EPHX1 ) [6]. Meanwhile, the genetic variants ofc.337T>C (rs1051740) and c.416A>G (rs2234922) in EPHX1 were found associated with the pharmacokinetics and pharmacodynamics of CBZ [7, 8]. P-glycoprotein (P-gp), producted by ATP binding cassette transporter, subfamily B, member 1 (ABCB1 ) or multidrug resistance 1 gene (MDR1 ), is a highly reported drug efflux transporter as CBZ substrates [9-11]. As a highly polymorphic drug-resistance gene, the ABCB1 polymorphisms ofc.3435C>T (rs1045642) in exon 26,c.1236C>T (rs1128503) in exon 12 andc.2677G>T/A (rs2032582) in exon 21 have been extensively studied can influence the extent of expression and transport activities of P-gp [11]. The c.3184A>G (rs2298771) and IVS5-91G>A (rs381278) polymorphisms in SCN1A alter the sodium channels structure and functions relationship with CBZ, ultimately rendering them insensitive to the blocking effect of CBZ, and SCN1A polymorphisms has been found to be associated with CBZ-resistant epilepsy [12-14].
In 2019, Gui-Xin Zhao et al. [15] performed a meta-analysis revealed an association between EPHX1 c.337T>C andc.416A>G polymorphisms and CBZ metabolism in epilepsy with 7 articles were included, but the CDRCBZdata units were inconsistent in the Chin-Chuan Hung [16] and Chun-Lai Ma [17] studies were also directly meta-analyzed, which will bring a huge deviation in the outcome. Meanwhile, the relationship between ABCB1 (C.3435C>T, c.2677G>T/A and c.1236C>T) , EPHX1 (c.337T>Cand c.416A>G) polymorphisms and CBZ resistance still remains contradictory. In order to realize the individualized treatment of CBZ in epileptic patients, we performed a systematic meta-analysis to evaluate the effects of ABCB1 (C.3435C>T, c.2677G>T/A and c.1236C>T) and EPHX1 (c.337T>C and c.416A>G) polymorphisms on CBZ metabolism and resistance.