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CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy

Djordjevic, Natasa; Milovanovic, Dragana Dragas; Radovanovic, Marija; Radosavljevic, Ivan; Obradovic, Slobodan; Jakovljevic, Mihajlo LU ; Milovanovic, Dragan; Milovanovic, Jasmina R and Jankovic, Slobodan (2016) In European Journal of Clinical Pharmacology 72(4). p.45-439
Abstract

PURPOSE: The purpose of this study is to investigate the effect of two of the most important functional CYP1A2 variations -3860G > A and -163C > A on carbamazepine pharmacokinetics in Serbian pediatric epileptic patients.

METHODS: The study involved 40 Serbian pediatric epileptic patients on steady-state carbamazepine treatment. Genotyping for -3860G > A and -163C > A was carried out using PCR-RFLP method, and carbamazepine plasma concentrations were determined by high pressure liquid chromatography (HPLC) method. For pharmacokinetic analysis, NONMEM software with implementation of ADVAN 1 subroutine was used.

RESULTS: CYP1A2 polymorphism -163C > A was found at the frequency of 65.0 %, while -3860G > A was... (More)

PURPOSE: The purpose of this study is to investigate the effect of two of the most important functional CYP1A2 variations -3860G > A and -163C > A on carbamazepine pharmacokinetics in Serbian pediatric epileptic patients.

METHODS: The study involved 40 Serbian pediatric epileptic patients on steady-state carbamazepine treatment. Genotyping for -3860G > A and -163C > A was carried out using PCR-RFLP method, and carbamazepine plasma concentrations were determined by high pressure liquid chromatography (HPLC) method. For pharmacokinetic analysis, NONMEM software with implementation of ADVAN 1 subroutine was used.

RESULTS: CYP1A2 polymorphism -163C > A was found at the frequency of 65.0 %, while -3860G > A was not detected. The correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in carriers of -163C/C and C/A genotypes (r = 0.68, p = 0.0004). The equation that described population clearance (CL) was CL (l/h) = 0.176 + 0.0484 * SEX + 0.019 * CYP1A2 + 0.000156 * DD, where SEX has a value of 1 if male and 0 if female, CYP1A2 has a value of 1 if -163A/A and 0 if -163C/C or C/A, and DD is the total carbamazepine daily dose (mg/day).

CONCLUSIONS: CYP1A2 -163A/A genotype influence carbamazepine pharmacokinetics. In addition to sex and total carbamazepine daily dose, -163C > A CYP1A2 polymorphism should be considered as a predictor of carbamazepine clearance.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Adolescent, Carbamazepine/pharmacokinetics, Child, Child, Preschool, Cytochrome P-450 CYP1A2/genetics, Epilepsy/drug therapy, Female, Genotype, Humans, Male, Polymorphism, Genetic/genetics
in
European Journal of Clinical Pharmacology
volume
72
issue
4
pages
45 - 439
publisher
Springer
external identifiers
  • scopus:84954308407
ISSN
1432-1041
DOI
10.1007/s00228-015-2006-9
language
English
LU publication?
no
id
862239a1-6256-455e-8129-50393467f239
date added to LUP
2018-09-01 22:48:38
date last changed
2018-09-09 05:01:28
@article{862239a1-6256-455e-8129-50393467f239,
  abstract     = {<p>PURPOSE: The purpose of this study is to investigate the effect of two of the most important functional CYP1A2 variations -3860G &gt; A and -163C &gt; A on carbamazepine pharmacokinetics in Serbian pediatric epileptic patients.</p><p>METHODS: The study involved 40 Serbian pediatric epileptic patients on steady-state carbamazepine treatment. Genotyping for -3860G &gt; A and -163C &gt; A was carried out using PCR-RFLP method, and carbamazepine plasma concentrations were determined by high pressure liquid chromatography (HPLC) method. For pharmacokinetic analysis, NONMEM software with implementation of ADVAN 1 subroutine was used.</p><p>RESULTS: CYP1A2 polymorphism -163C &gt; A was found at the frequency of 65.0 %, while -3860G &gt; A was not detected. The correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in carriers of -163C/C and C/A genotypes (r = 0.68, p = 0.0004). The equation that described population clearance (CL) was CL (l/h) = 0.176 + 0.0484 * SEX + 0.019 * CYP1A2 + 0.000156 * DD, where SEX has a value of 1 if male and 0 if female, CYP1A2 has a value of 1 if -163A/A and 0 if -163C/C or C/A, and DD is the total carbamazepine daily dose (mg/day).</p><p>CONCLUSIONS: CYP1A2 -163A/A genotype influence carbamazepine pharmacokinetics. In addition to sex and total carbamazepine daily dose, -163C &gt; A CYP1A2 polymorphism should be considered as a predictor of carbamazepine clearance.</p>},
  author       = {Djordjevic, Natasa and Milovanovic, Dragana Dragas and Radovanovic, Marija and Radosavljevic, Ivan and Obradovic, Slobodan and Jakovljevic, Mihajlo and Milovanovic, Dragan and Milovanovic, Jasmina R and Jankovic, Slobodan},
  issn         = {1432-1041},
  keyword      = {Adolescent,Carbamazepine/pharmacokinetics,Child,Child, Preschool,Cytochrome P-450 CYP1A2/genetics,Epilepsy/drug therapy,Female,Genotype,Humans,Male,Polymorphism, Genetic/genetics},
  language     = {eng},
  number       = {4},
  pages        = {45--439},
  publisher    = {Springer},
  series       = {European Journal of Clinical Pharmacology},
  title        = {CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy},
  url          = {http://dx.doi.org/10.1007/s00228-015-2006-9},
  volume       = {72},
  year         = {2016},
}