4 Discussion
As a clinical first-line antiepileptic drug, CBZ has a relatively narrow
therapeutic range (4–12μg/mL) and wide inter-individual variability
[34]. Genetic variants in ABCB1, EPHX1, SCN1A genes are
wellknown to influence the individual CBZ daily maintenance doses,
metabolism and resistance for epileptic patients. Thus, clarify the role
of ABCB1, EPHX1, SCN1A genetic polymorphisms in pharmacokinetics
and pharmacodynamics of CBZ will be helpful for the effective clinical
individualized treatment of epilepsy.
The ABCB1 (c.3435C>T, c.2677G>T/A and
c.1236C>T) in exon 26 closely related with the altered
expression levels of P-gp, range of CBZ resistance in epileptics. In the
meta-analysis, c.3435C>T andc.2677G>T/A polymorphisms were found to be
associated with adjusted concentrations of CBZ. For the high
heterogeneity in c.2677G>T/A , we did not conduct
subgroup analysis or sensitivity analysis limited by only 3 articles
included. In order to seek the mechanism ofc.3435C>T on the clinical effect of CBZ in epilepsy
patients, we further analyzed whether c.3435C>Tpolymorphism change the clinical efficacy by influencing CBZ resistance,
and found that patients with the c.3435C>T TTgenotype exhibited lower CDZ resistance compared with CT or(CT + CC) genotype, Hongmei Meng’s study [29] also supported
it. This might attributable to the CC genotype ofc.3435C>T enhancing the expression of P-gp and
excessive CBZ efflux across the blood-brain barrier (BBB) resulting in
drug resistance in epileptics. However, the included studies of Armond
Daci [8] and Gulay Oner Ozgon’s [30] results unsupported it in
Kosovar Albanian and Turkey epileptic patients. This phenomenon may be
attribute to ethnic differences, but we did not conduct racial analysis
limited number of literatures included. Overall, our results confirmedc.3435C>T polymorphism may influence the clinical
efficacy via regulating CBZ resistance followed by adjusting serum
concentration of CBZ although more high-quality original studies are
still required.
As an active metabolites of CBZ, CBZ-10,11-epoxide (CBZE) is further
transformed to an inactive metabolite, CBZ-10,11-diol (CBZD) via
microsomal epoxide hydrolase (mEH) which encoded by EPHX1 [35, 36].
Thus, EPHX1 (c.337T>C and c.416A>G)mutation may affect CBZ pharmocokinetics and pharmacodynamics by
changing the function of mEH [36, 37]. Our study found that the
patients with AA genotype in c.416A>G has
lower level of CDRCBZD, prompting that CBZ metabolism
may be inhibited by the c.416A>G variant [37],
which has been demonstrated to decrease mEH activity in Yukiko
Nakajima’s study [38]. However, no association between any genetic
models of EPHX1 c.416A>G polymorphism and CBZ
resistance was found, which supported by Wenting Yun et al. study
[25]. In addition, we abandoned high heterogeneity data of
CDRCBZE (for c.337T>C ) and the
instability data of CDRCBZD : CDRCBZEratio (for c.416A>G ) limited by 2 articles with
small samples. Furthermore, no association was found between EPHX1
c.416A>G and CBZ resistance in our present study.
Therefore, EPHX1 c.416A>G associated with CBZ
metabolism and resistance need to be further studied in the larger
cohorts of CBZ for epilepsy.
IVS5-91G>A located at 5 splice donor site ofSCN1A exon 5N, plays a crucial role in epilepsy by encoding the
S4 transmembrane segment or voltage sensor in the first domain of the
Nav1.1 protein and initiating action potentials in neurons in different
parts of the mammalian brain [39, 40]. Whilec.3184A>G polymorphism in SCN1A may influence
the structural and functional properties of sodium channels and further
impact treatment of CBZ for epilepsy via converting threonine to alanine
[24]. It was noteworthy that, no association was found based on the
present included studies containing Chinese, Japanese, Serbia, and
Pakistan epilepsy patients among SCN1A (c.3184A>G and
IVS5-91G>A) and CBZ resistance, which cannot be further
supported by CBZ metabolism for small numbers of literatures and samples
included. This may be due to the lack of data for further evaluation
differences in the geographical distribution of the subjects or
environmental factors [41]. Consequently, further investigations
based on more well-designed experiments and larger sample size should be
performed to verify the effects of SCN1A (c.3184A>G
and IVS5-91G>A) on CBZ resistance and metabolism.
This meta-analysis first comprehensively collected the existing studies
and reviewed the relationships among ABCB1
(c.3435C>T) , EPHX1 (c.337T>C and
c.416A>G) , SCN1A (c.3184A>G and
IVS5-91G>A) polymorphisms and CBZ metabolisms and
resistance. Compared with precious meta-analysis [15], the present
study not only evaluated the associations between the ABCB1
(c.3435C>T) , EPHX1 (c.337T>C and
c.416A>G) , SCN1A (c.3184A>G and
IVS5-91G>A) polymorphisms and drug-resistance risk, but
also clarified the effect of corresponding genes on CBZ metabolism in
epileptics. Consequently, our data suggest that ABCB1
c.3435C>T and EPHX1 c.416A>Gpolymorphisms could influence inter-individual variability of CBZ
metabolism and resistance.
The inconsistencies in the studies may be explained by some phenomena.
Firstly, only English and Chinese studies were included, many
literatures in other languages were ignored which may lead to the
existence of bias. Secondly, the small sample size may result in
false-positive problem and weaken the statistical power. Thirdly, the
optimal dosage of CBZ may be influenced by a variety of confounding
factors such as age, sex, ethnicity, and the interaction between gene
mutations, but the lack of original data limited our ability to further
assess these factors. Fourthly, lack of some important raw data limits
the further evaluation of other indicators, such as the therapeutic
effect of concentration-time curves on metabolic clearance and adverse
events. Furthermore, based on Egger’s test, we detected a small
publication bias which might be caused by unpublished data, because
negative studies were less likely to be published and included in
journals and computerized database, and only studies indexed by the
selected databases were included, this results in a potential
overestimation of effect sizes. Finally, different doses and treatment
durations were used in the included studies, which may affect the
observable effect of pharmacokinetic genes. These caveats should be
considered and overcome in future large sample and multiracial studies.
In spite of above potential limitations, our meta-analysis collected the
most recently published data on the association between ABCB1,
EPHX1 gene polymorphisms and CBZ metabolism and resistance.