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CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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 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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Acknowledgments

The study was financially 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.

Contributions of authors’ statement

• Natasa Djordjevic participated in conception and design of the work, as well as in acquisition, analysis, and interpretation of the data, wrote the paper, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Dragana Dragas Milovanovic participated in acquisition, analysis, and interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Marija Radovanovic participated in acquisition, analysis, and interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Ivan Radosavljevic participated in acquisition, analysis, and interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Slobodan Obradovic participated in conception and design of the work, as well as in interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Mihajlo Jakovljevic participated in analysis and interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Dragan Milovanovic participated in acquisition, analysis, and interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Jasmina R. Milovanovic participated in conception and design of the work, as well as in acquisition, analysis, and interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

• Slobodan Jankovic participated in analysis and interpretation of the data, revised the paper critically for important intellectual content, approved the submitted version of the paper, and agrees to be accountable for all aspects of the work.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia

    Natasa Djordjevic, Dragana Dragas Milovanovic, Mihajlo Jakovljevic, Dragan Milovanovic, Jasmina R. Milovanovic & Slobodan Jankovic

  2. Department of Pediatrics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia

    Marija Radovanovic & Slobodan Obradovic

  3. Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia

    Ivan Radosavljevic

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  1. Natasa Djordjevic
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  2. Dragana Dragas Milovanovic
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Correspondence to Natasa Djordjevic.

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Djordjevic, N., Milovanovic, D.D., Radovanovic, M. et al. CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy. Eur J Clin Pharmacol 72, 439–445 (2016). https://doi.org/10.1007/s00228-015-2006-9

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  • DOI: https://doi.org/10.1007/s00228-015-2006-9

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