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.