THE INFLUENCE OF CYP2C8*3 ON CARBAMAZEPINE SERUM
CONCENTRATION IN EPILEPTIC PEDIATRIC PATIENTS
Milovanovic DD, Milovanovic JR, Radovanovic M, Radosavljevic I,
Obradovic S, Jankovic S, Milovanovic D, Djordjevic N
*Corresponding Author: M.D., Ph.D., Associate Professor, Department of Pharmacology
and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000 Kragujevac,
Serbia. Tel: +381-34-306-800, ext 223. Fax: +381-34-306-800. E-mail: natashadj2002@yahoo.com
page: 21
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DISCUSSION
The present study investigated the distribution
frequency of CYP2C8 variations *3 (g.416G>A) and
*5 (g.475delA), and their influence on carbamazepine
dosing, serum concentration and clearance, in Serbian
epileptic pediatric patients. Additionally, we estimated
the effect of standard covariates such as body
weight, age, sex, total daily dose of carbamazepine
and other anticonvulsants on carbamazepine clearance.
The results rendered sex and total carbamazepine
daily dose relevant for carbamazepine treatment.
The CYP2C8 genetic polymorphism significantly
affects carbamazepine metabolism, but its role seems
not to be clinically important.
CYP2C8 is a phase I metabolizing enzyme
involved in biotransformation of numerous drugs
[12,13]. Although not the major role player in carbamazepine
pharmacokinetics, it is considered to be of
importance as it promotes conversion of the drug to its
active metabolite carbamazepine-10,11-epoxide [14].
In addition, the CYP2C8 enzyme is inducible, with
the induction mediated, among others, by pregnane
X and the constitutive androstane receptor [15]. As
both of these receptors might be activated by carbamazepine
[16,17], it could be speculated that the contribution
of CYP2C8 in carbamazepine metabolism
is more complicated compared to its other substrates.
Therefore, the polymorphism of the CYP2C8 coding
gene could partly explain observed inter-individual
variation in response to carbamazepine treatment
[18]. In Caucasians, CYP2C8*3 (g.416G>A) is the
most common nonsynonymous variant, frequently
associated with decreased enzyme activity [12]. On
the other hand, CYP2C8 *5 (g.475delA) belongs to
rare variations, but raises attention as one of the few
that yield highly truncated and most probably completely
inactive enzyme [19]. Based on the present
study, the frequencies of CYP2C8*3 and CYP2C8 *5
polymorphisms in the Serbian population are in accordance
with the data obtained from other Caucasian
populations [5,20-22].
Effects of the CYP2C8 polymorphism on drug
metabolism have already been investigated [6,21-26].
Although the activity of the most frequent CYP2C8
variant *3 appears to be substrate-dependent [6],
its influence on carbamazepine pharmacokinetics
was not explored. In the present study, there was
a tendency toward lower daily dose and higher serum
concentrations of carbamazepine in CYP2C8*3
carriers, indicating decreased enzyme activity and
slower metabolism of the drug. In addition, the observed
correlation between carbamazepine dose and
concentration was found to be significant only in
carriers of the CYP2C8 wild type allele. The lack of
similar correlation in the presence of the *3 variant
suggests the existence of other factors that might
affect carbamazepine pharmacokinetics, e.g., by altering
the binding activity of the variant CYP2C8
enzyme [27]. Another plausible explanations might
include the possible dose-dependent autoinduction of carbamazepine CYP2C8-mediated metabolism [28],
and/or the linkage disequilibrium between *3 and
other CYP2C8 alleles [18]. Regardless of the cause,
the presented findings render CYP2C8*3 carriers especially
susceptible to an unpredictable reaction to
carbamazepine, and therefore, good candidates for a
closer follow-up during treatment, especially as the
drug concentration in these patients proved not to be
sufficient to guide the dose adjustment.
To further test whether CYP2C8*3 genotyping
should be considered as a routine analysis in patients
on carbamazepine, population pharmacokinetic
analysis was performed. Numerous pharmacokinetic
models are already available from the literature dealing
with carbamazepine clearance [29-32]. Bearing
in mind that carbamazepine is the most frequently
used anticonvulsant in Serbia [10], we considered it
relevant to evaluate the CYP2C8 genetic polymorphism
in a pharmacokinetic model in Serbian epileptic
pediatric patients. Population pharmacokinetic
analysis, which included CYP2C8*3 genotype as a
covariate, failed to demonstrate a significant effect of
genetic polymorphism on carbamazepine clearance.
Unlike some other drug therapies investigated so far
[21,22,24], our study showed that CYP2C8 might
be of lesser clinical importance to carbamazepine
treatment. Yet, the rather small sample size limited
the generality of our findings, and additional studies,
involving more subjects and also other populations,
would be required for a better understanding of
CYP2C8 polymorphism effects on epileptic patients’
reaction to carbamazepine.
Other findings of our population pharmacokinetic
analysis included sex and total carbamazepine daily
dose as significant indicators of carbamazepine clearance.
The observed effect of sex has been previously
reported, with girls having lower values for clearance,
most probably due to estrogen influence on microsomal
enzymes activity [28,33,34]. However, most
of the authors did not show such differences, thus the
predictive value of sex for carbamazepine clearance
remains controversial [10,30,35-38]. On the contrary,
most of the studies denoted positive correlation of
carbamazepine daily dose with the drug clearance
[32,39,40], and our results confirm those reports.
In conclusion, our results do not support routine
genotyping of CYP2C8 in Serbian epileptic pediatric
patients on carbamazepine treatment. Yet, significantly
higher serum concentrations in CYP2C8*3
carriers confirm the importance of CYP2C8 genetic
polymorphism for carbamazepine pharmacokinetics,
warranting further investigations.
Declaration of Interest. This study was supported
by the Faculty of Medical Sciences, University
of Kragujevac, Serbia, JP 07/11, and the Ministry of
Science and Technology of the Republic of Serbia,
grants No. 175007 and 175056. The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of this article.
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