Skip to main content
Log in

Pharmacokinetics and Pharmacogenetics of Carbamazepine in Children

  • Review Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Although carbamazepine is one of the oldest anticonvulsant drugs, it is still heavily utilized for treatment of epilepsy in children. The aim of this article was to review the current knowledge about pharmacokinetics and pharmacogenetics of carbamazepine in children. The literature for this review was systematically searched for in the MEDLINE and SCINDEKS databases. Oral bioavailability of carbamazepine in children is about 75–85%, and it is approximately 75–85% bound to plasma proteins. Apparent volume of distribution is 1.2–1.9 l/kg and total clearance between 0.05 and 0.1 l/h/kg. Pharmacokinetics of carbamazepine in children is age and body weight dependent and highly variable due to influence of dosing regimen and co-medication. The current evidence on the importance of pharmacogenetics for carbamazepine efficacy and safety in children supports the association of PXR*1B, HNF4a rs2071197, CYP1A2*1F, ABCC2 1249G>A, and PRRT2 c.649dupC with either pharmacokinetics or pharmacodynamics of carbamazepine. The importance of human leukocyte antigen (HLA) typing for prediction of adverse drug reactions to carbamazepine in children is also confirmed. Both genetic and environmental factors are responsible for shaping pharmacokinetics and pharmacodynamics of carbamazepine in children. To ensure safe and effective use of carbamazepine in this population, physicians should adjust dosing regimen according to existing pattern of genetic and environmental influences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bielen I, Sruk A, Planjar-Prvan M, et al. Age-related pattern of the antiepileptic drug utilization in active epilepsy: a population-based survey. Coll Antropol. 2009;33(2):659–63.

    PubMed  Google Scholar 

  2. Albsoul-Younes A, Gharaibeh L, Murtaja AA, et al. Patterns of antiepileptic drugs use in epileptic pediatric patients in Jordan. Neurosciences (Riyadh). 2016;21(3):264–7.

    Article  Google Scholar 

  3. Habib M, Khan SU, Hoque A, et al. Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital. BMC Res Notes. 2013;6:473.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cohen SA, Lawson JA, Graudins LV, et al. Changes in anticonvulsant prescribing for Australian children: implications for Quality Use of Medicines. J Paediatr Child Health. 2012;48(6):490–5.

    Article  PubMed  Google Scholar 

  5. Kwong KL, Tsui KW, Wu SP, et al. Utilization of antiepileptic drugs in Hong Kong children. Pediatr Neurol. 2012;46(5):281–6.

    Article  PubMed  Google Scholar 

  6. Landmark CJ, Fossmark H, Larsson PG, et al. Prescription patterns of antiepileptic drugs in patients with epilepsy in a nation-wide population. Epilepsy Res. 2011;95(1–2):51–9.

    Article  PubMed  Google Scholar 

  7. Seetharam MN, Pellock JM. Risk-benefit assessment of carbamazepine in children. Drug Saf. 1991;6(2):148–58.

    Article  CAS  PubMed  Google Scholar 

  8. Djordjevic N, Milovanovic DD, Radovanovic M, et al. CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy. Eur J Clin Pharmacol. 2016;72(4):439–45.

    Article  CAS  PubMed  Google Scholar 

  9. Milovanovic JR, Jankovic SM. Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis. Int J Clin Pharmacol Ther. 2011;49(7):428–36.

    Article  CAS  PubMed  Google Scholar 

  10. Jankovic SM, Jovanovic D, Milovanovic JR. Pharmacokinetic modeling of carbamazepine based on clinical data from Serbian epileptic patients. Methods Find Exp Clin Pharmacol. 2008;30(9):707–13.

    Article  CAS  PubMed  Google Scholar 

  11. Dudley RW, Penney SJ, Buckley DJ. First-drug treatment failures in children newly diagnosed with epilepsy. Pediatr Neurol. 2009;40(2):71–7.

    Article  PubMed  Google Scholar 

  12. Carlsson KC, Hoem NO, Glauser T, Vinks AA. Development of a population pharmacokinetic model for carbamazepine based on sparse therapeutic monitoring data from pediatric patients with epilepsy. Clin Ther. 2005;27(5):618–26.

    Article  CAS  PubMed  Google Scholar 

  13. Bondareva IB, Sokolov AV, Tischenkova IF, Jelliffe RW. Population pharmacokinetic modelling of carbamazepine by using the iterative Bayesian (IT2B)and the nonparametric EM (NPEM) algorithms: implications for dosage. J Clin Pharm Ther. 2001;26(3):213–23.

    Article  CAS  PubMed  Google Scholar 

  14. MacKichan JJ, Zola EM. Determinants of carbamazepine and carbamazepine 10,11-epoxide binding to serum protein, albumin and alpha 1-acid glycoprotein. Br J Clin Pharmacol. 1984;18(4):487–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arvidsson J, Nilsson HL, Sandstedt P, et al. Replacing carbamazepine slow-release tablets with carbamazepine suppositories: a pharmacokinetic and clinical study in children with epilepsy. J Child Neurol. 1995;10(2):114–7.

    Article  CAS  PubMed  Google Scholar 

  16. Miles MV, Lawless ST, Tennison MB, et al. Rapid loading of critically ill patients with carbamazepine suspension. Pediatrics. 1990;86(2):263–6.

    CAS  PubMed  Google Scholar 

  17. Summers B, Summers RS. Carbamazepine clearance in paediatric epilepsy patients. Influence of body mass, dose, sex and co-medication. Clin Pharmacokinet. 1989;17(3):208–16.

    Article  CAS  PubMed  Google Scholar 

  18. Hartley R, Forsythe WI, McLain B, et al. Daily variations in steady-state plasma concentrations of carbamazepine and its metabolites in epileptic children. Clin Pharmacokinet. 1991;20(3):237–46.

    Article  CAS  PubMed  Google Scholar 

  19. Paxton JW, Aman MG, Werry JS. Fluctuations in salivary carbamazepine and carbamazepine-10,11-epoxide concentrations during the day in epileptic children. Epilepsia. 1983;24(6):716–24.

    Article  CAS  PubMed  Google Scholar 

  20. Singh B, Singh P, al Hifzi I, et al. Treatment of neonatal seizures with carbamazepine. J Child Neurol. 1996;11(5):378–82.

  21. Battino D, Bossi L, Croci D, et al. Carbamazepine plasma levels in children and adults: influence of age, dose, and associated therapy. Ther Drug Monit. 1980;2(4):315–22.

    Article  CAS  PubMed  Google Scholar 

  22. Peytchev L, Chakova L. Comparative drug monitoring of carbamazepin suspension (TroyaPharm) and Tegretol syrup (Ciba Geigy) in epileptic children. Folia Med (Plovdiv). 1998;40(4):29–33.

    CAS  PubMed  Google Scholar 

  23. Morselli PL, Monaco F, Gerna M, et al. Bioavailability of two carbamazepine preparations during chronic administration to epileptic patients. Epilepsia. 1975;16(5):759–64.

    Article  CAS  PubMed  Google Scholar 

  24. Cornaggia C, Gianetti S, Battino D, et al. Comparative pharmacokinetic study of chewable and conventional carbamazepine in children. Epilepsia. 1993;34(1):158–60.

    Article  CAS  PubMed  Google Scholar 

  25. Thakker KM, Mangat S, Garnett WR, et al. Comparative bioavailability and steady state fluctuations of Tegretol commercial and carbamazepine OROS tablets in adult and pediatric epileptic patients. Biopharm Drug Dispos. 1992;13(8):559–69.

    Article  CAS  PubMed  Google Scholar 

  26. Pieters MS, Jennekens-Schinkel A, Stijnen T, et al. Carbamazepine (CBZ) controlled release compared with conventional CBZ: a controlled study of attention and vigilance in children with epilepsy. Epilepsia. 1992;33(6):1137–44.

    Article  CAS  PubMed  Google Scholar 

  27. Eeg-Olofsson O, Nilsson HL, Tonnby B, et al. Diurnal variation of carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva in children with epilepsy: a comparison between conventional and slow-release formulations. J Child Neurol. 1990;5(2):159–65.

    Article  CAS  PubMed  Google Scholar 

  28. Ryan SW, Forsythe I, Hartley R, et al. Slow release carbamazepine in treatment of poorly controlled seizures. Arch Dis Child. 1990;65(9):930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Emich-Widera E, Likus W, Kazek B, et al. CYP3A5*3 and C3435T MDR1 polymorphisms in prognostication of drug-resistant epilepsy in children and adolescents. Biomed Res Int. 2013;2013:526837.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Ufer M, von Stulpnagel C, Muhle H, et al. Impact of ABCC2 genotype on antiepileptic drug response in Caucasian patients with childhood epilepsy. Pharmacogenet Genomics. 2011;21(10):624–30.

    Article  CAS  PubMed  Google Scholar 

  31. Potschka H, Fedrowitz M, Loscher W. P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. NeuroReport. 2001;12(16):3557–60.

    Article  CAS  PubMed  Google Scholar 

  32. Kodama Y, Kuranari M, Kodama H, et al. In vivo determinations of carbamazepine and carbamazepine-10, 11-epoxide binding parameters to serum proteins in monotherapy patients. J Clin Pharmacol. 1993;33(9):851–5.

    Article  CAS  PubMed  Google Scholar 

  33. Contin M, Riva R, Albani F, et al. Alpha 1-acid glycoprotein concentration and serum protein binding of carbamazepine and carbamazepine-10,11 epoxide in children with epilepsy. Eur J Clin Pharmacol. 1985;29(2):211–4.

    Article  CAS  PubMed  Google Scholar 

  34. Kodama Y, Kuranari M, Kodama H, et al. Evaluation of equations for unbound serum concentration prediction of carbamazepine and carbamazepine-10,11-epoxide in polytherapy pediatric patients with epilepsy. J Pharm Sci. 1995;84(7):835–9.

    Article  CAS  PubMed  Google Scholar 

  35. Pynnönen S, Sillanpää M, Frey H, Iisalo E. Carbamazepine and its 10,11-epoxide in children and adults with epilepsy. Eur J Clin Pharmacol. 1977;11(2):129–33.

    Article  PubMed  Google Scholar 

  36. MacKichan JJ, Duffner PK, Cohen ME. Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11-epoxide in epileptic patients. Br J Clin Pharmacol. 1981;12(1):31–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Moreland TA, Priestman DA, Rylance GW. Saliva carbamazepine levels in children before and during multiple dosing. Br J Clin Pharmacol. 1982;13(5):647–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kodama Y, Tsutsumi K, Kuranari M, et al. In vivo binding characteristics of carbamazepine and carbamazepine-10,11-epoxide to serum proteins in paediatric patients with epilepsy. Eur J Clin Pharmacol. 1993;44(3):291–3.

    Article  CAS  PubMed  Google Scholar 

  39. Minami T, Ieiri I, Ohtsubo K, et al. Influence of additional therapy with zonisamide (Excegran) on protein binding and metabolism of carbamazepine. Epilepsia. 1994;35(5):1023–5.

    Article  CAS  PubMed  Google Scholar 

  40. Bertilsson L, Höjer B, Tybring G, et al. Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique. Clin Pharmacol Ther. 1980;27(1):83–8.

    Article  CAS  PubMed  Google Scholar 

  41. Delgado Iribarnegaray MF, Santo Bueldga D, García Sánchez MJ, et al. Carbamazepine population pharmacokinetics in children: mixed-effect models. Ther Drug Monit. 1997;19(2):132–9.

    Article  CAS  PubMed  Google Scholar 

  42. Reith DM, Appleton DB, Hooper W, Eadie MJ. The effect of body size on the metabolic clearance of carbamazepine. Biopharm Drug Dispos. 2000;21(3):103–11.

    Article  CAS  PubMed  Google Scholar 

  43. Dragas Milovanovic D, Radosavljevic I, Radovanovic M, et al. CYP3A5 polymorphism in Serbian paediatric epileptic patients on carbamazepine treatment. SJECR. 2015;16(2):93–9.

    Google Scholar 

  44. Altafullah I, Talwar D, Loewenson R, et al. Factors influencing serum levels of carbamazepine and carbamazepine-10,11-epoxide in children. Epilepsy Res. 1989;4(1):72–80.

    Article  CAS  PubMed  Google Scholar 

  45. Korinthenberg R, Haug C, Hannak D. The metabolization of carbamazepine to CBZ-10,11-epoxide in children from the newborn age to adolescence. Neuropediatrics. 1994;25(4):214–6.

    Article  CAS  PubMed  Google Scholar 

  46. Lanchote VL, Bonato PS, Campos GM, Rodrigues I. Factors influencing plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide in epileptic children and adults. Ther Drug Monit. 1995;17(1):47–52.

    Article  CAS  PubMed  Google Scholar 

  47. Liu H, Delgado MR. Interactions of phenobarbital and phenytoin with carbamazepine and its metabolites’ concentrations, concentration ratios, and level/dose ratios in epileptic children. Epilepsia. 1995;36(3):249–54.

    Article  CAS  PubMed  Google Scholar 

  48. Liu H, Delgado MR. Improved therapeutic monitoring of drug interactions in epileptic children using carbamazepine polytherapy. Ther Drug Monit. 1994;16(2):132–8.

    Article  CAS  PubMed  Google Scholar 

  49. Robbins DK, Wedlund PJ, Kuhn R, et al. Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine. Br J Clin Pharmacol. 1990;29(6):759–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Farwell JR, Anderson GD, Kerr BM, Tor JA, Levy RH. Stiripentol in atypical absence seizures in children: an open trial. Epilepsia. 1993;34(2):305–11.

    Article  CAS  PubMed  Google Scholar 

  51. Cazali N, Tran A, Treluyer JM, Rey E, d’Athis P, Vincent J, Pons G. Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human. Br J Clin Pharmacol. 2003;56(5):526–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. McKauge L, Tyrer JH, Eadie MJ. Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma. Ther Drug Monit. 1981;3(1):63–70.

    Article  CAS  PubMed  Google Scholar 

  53. Sánchez A, Durán JA, Serrano JS. Steady-state carbamazepine plasma concentration-dose ratios in epileptic patients. Clin Pharmacokinet. 1986;11(5):411–4.

    Article  PubMed  Google Scholar 

  54. Liu H, Delgado MR. A comprehensive study of the relation between serum concentrations, concentration ratios, and level/dose ratios of carbamazepine and its metabolites with age, weight, dose, and clearances in epileptic children. Epilepsia. 1994;35(6):1221–9.

    Article  CAS  PubMed  Google Scholar 

  55. Yukawa E, Hokazono T, Satou M, et al. Pharmacokinetic interactions among phenobarbital, carbamazepine, and valproic acid in pediatric Japanese patients: clinical considerations on steady-state serum concentration-dose ratios. Am J Ther. 2000;7(5):303–8.

    Article  CAS  PubMed  Google Scholar 

  56. Yukawa E, Suzuki A, Higuchi S, Aoyama T. Influence of age and co-medication on steady-state carbamazepine serum level-dose ratios in Japanese paediatric patients. J Clin Pharm Ther. 1992;17(1):65–9.

    Article  CAS  PubMed  Google Scholar 

  57. Furlanut M, Montanari G, Bonin P, Casara GL. Carbamazepine and carbamazepine-10,11-epoxide serum concentrations in epileptic children. J Pediatr. 1985;106(3):491–5.

    Article  CAS  PubMed  Google Scholar 

  58. Rane A, Höjer B, Wilson JT. Kinetics of carbamazepine and its 10,11-epoxide metabolite in children. Clin Pharmacol Ther. 1976;19(3):276–83.

    Article  CAS  PubMed  Google Scholar 

  59. Bourgeois BF, Wad N. Carbamazepine-10,11-diol steady-state serum levels and renal excretion during carbamazepine therapy in adults and children. Ther Drug Monit. 1984;6(3):259–65.

    Article  CAS  PubMed  Google Scholar 

  60. Albani F, Riva R, Contin M, Baruzzi A. A within-subject analysis of carbamazepine disposition related to development in children with epilepsy. Ther Drug Monit. 1992;14(6):457–60.

    Article  CAS  PubMed  Google Scholar 

  61. Suzuki Y, Cox S, Hayes J, Walson PD. Carbamazepine age-dose ratio relationship in children. Ther Drug Monit. 1991;13(3):201–8.

    Article  CAS  PubMed  Google Scholar 

  62. Elyas AA, Patsalos PN, Agbato OA, et al. Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-10,11-epoxide in serum of children with epilepsy. Ther Drug Monit. 1986;8(3):288–92.

    Article  CAS  PubMed  Google Scholar 

  63. Riva R, Contin M, Albani F, Perucca E, Lamontanara G, Baruzzi A. Free and total serum concentrations of carbamazepine and carbamazepine-10,11-epoxide in infancy and childhood. Epilepsia. 1985;26(4):320–2.

    Article  CAS  PubMed  Google Scholar 

  64. Gray AL, Botha JH, Miller R. A model for the determination of carbamazepine clearance in children on mono- and polytherapy. Eur J Clin Pharmacol. 1998;54(4):359–62.

    Article  CAS  PubMed  Google Scholar 

  65. Eichelbaum M, Tomson T, Tybring G, Bertilsson L. Carbamazepine metabolism in man. Induction and pharmacogenetic aspects. Clin Pharmacokinet. 1985;10(1):80–90.

    Article  CAS  PubMed  Google Scholar 

  66. ICH Topic E15. Definitions for genomic biomarkers, pharmacogenomics, pharmacogenetics, genomic data and sample coding categories. European Medicines Agency, EMEA/CHMP/ICH/437986/2006, November 2007. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002880.pdf. Accessed 23 Dec 2016.

  67. Council NR. Toward precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease. Washington, DC: National Academies Press (US); 2011. p. 128.

  68. Wang P, Yin T, Ma HY, et al. Effects of CYP3A4/5 and ABCB1 genetic polymorphisms on carbamazepine metabolism and transport in Chinese patients with epilepsy treated with carbamazepine in monotherapy and bitherapy. Epilepsy Res. 2015;117:52–7.

    Article  CAS  PubMed  Google Scholar 

  69. Khor AH, Lim KS, Tan CT, et al. HLA-B*15:02 association with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in an Indian population: a pooled-data analysis and meta-analysis. Epilepsia. 2014;55(11):e120–4.

    Article  CAS  PubMed  Google Scholar 

  70. Menzler K, Hermsen A, Balkenhol K, et al. A common SCN1A splice-site polymorphism modifies the effect of carbamazepine on cortical excitability–a pharmacogenetic transcranial magnetic stimulation study. Epilepsia. 2014;55(2):362–9.

    Article  CAS  PubMed  Google Scholar 

  71. Eichelbaum M, Bertilsson L, Lund L, et al. Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy. Eur J Clin Pharmacol. 1976;09(5–6):417–21.

    Article  CAS  PubMed  Google Scholar 

  72. Eichelbaum M, Ekbom K, Bertilsson L, et al. Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Eur J Clin Pharmacol. 1975;8(5):337–41.

    Article  CAS  PubMed  Google Scholar 

  73. Bertilsson L, Tomson T, Tybring G. Pharmacokinetics: time-dependent changes–autoinduction of carbamazepine epoxidation. J Clin Pharmacol. 1986;26(6):459–62.

    Article  CAS  PubMed  Google Scholar 

  74. Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation. Biochem Pharmacol. 1994;47(11):1969–79.

    Article  CAS  PubMed  Google Scholar 

  75. Pearce RE, Vakkalagadda GR, Leeder JS. Pathways of carbamazepine bioactivation in vitro I. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab Dispos. 2002;30(11):1170–9.

    Article  CAS  PubMed  Google Scholar 

  76. Pearce RE, Uetrecht JP, Leeder JS. Pathways of carbamazepine bioactivation in vitro: II. The role of human cytochrome P450 enzymes in the formation of 2-hydroxyiminostilbene. Drug Metab Dispos. 2005;33(12):1819–26.

    CAS  PubMed  Google Scholar 

  77. Pearce RE, Lu W, Wang Y, et al. Pathways of carbamazepine bioactivation in vitro. III. The role of human cytochrome P450 enzymes in the formation of 2,3-dihydroxycarbamazepine. Drug Metab Dispos. 2008;36(8):1637–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pelkonen O, Myllynen P, Taavitsainen P, et al. Carbamazepine: a ‘blind’ assessment of CVP-associated metabolism and interactions in human liver-derived in vitro systems. Xenobiotica. 2001;31(6):321–43.

    Article  CAS  PubMed  Google Scholar 

  79. Thorn CF, Leckband SG, Kelsoe J, et al. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics. 2011;21(12):906–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sadee W. The relevance of “missing heritability “ in pharmacogenomics. Clin Pharmacol Ther. 2012;92(4):428–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103–41.

    Article  CAS  PubMed  Google Scholar 

  82. Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 2001;11:773–9.

    Article  CAS  PubMed  Google Scholar 

  83. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–91.

    Article  CAS  PubMed  Google Scholar 

  84. Saruwatari J, Yoshida S, Tsuda Y, et al. Pregnane X receptor and hepatocyte nuclear factor 4alpha polymorphisms are cooperatively associated with carbamazepine autoinduction. Pharmacogenet Genomics. 2014;24(3):162–71.

    Article  CAS  PubMed  Google Scholar 

  85. Gao Y, Liu D, Wang H, et al. Functional characterization of five CYP2C8 variants and prediction of CYP2C8 genotype-dependent effects on in vitro and in vivo drug-drug interactions. Xenobiotica. 2010;40(7):467–75.

    Article  CAS  PubMed  Google Scholar 

  86. Ferguson SS, Chen Y, LeCluyse EL, et al. Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Mol Pharmacol. 2005;68(3):747–57.

    CAS  PubMed  Google Scholar 

  87. Dragas Milovanovic D, Milovanovic JR, Radovanovic M, et al. The influence of CYP2C8*3 on carbamazepine serum concentration in epileptic pediatric patients. BJMG. 2016;19(1):21–8.

    Google Scholar 

  88. Soyama A, Saito Y, Momamura K, et al. Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift. Drug Metab Pharmacokinet. 2002;17(4):374–7.

    Article  CAS  PubMed  Google Scholar 

  89. Kang P, Liao M, Wester MR, et al. CYP3A4-Mediated carbamazepine (CBZ) metabolism: formation of a covalent CBZ-CYP3A4 adduct and alteration of the enzyme kinetic profile. Drug Metab Dispos. 2008;36(3):490–9.

    Article  CAS  PubMed  Google Scholar 

  90. Sachse C, Brockmoller J, Bauer S, Roots I. Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999;47(4):445–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Aklillu E, Carrillo JA, Makonnen E, et al. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol. 2003;64(3):659–69.

    Article  CAS  PubMed  Google Scholar 

  92. Sim SC, Risinger C, Dahl ML, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006;79(1):103–13.

    Article  CAS  PubMed  Google Scholar 

  93. De Morais SM, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994;46(4):594–8.

    PubMed  Google Scholar 

  94. Djordjevic N, Ghotbi R, Jankovic S, Aklillu E. Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 −163C>A polymorphism. Eur J Clin Pharmacol. 2010;66:697–703.

    Article  CAS  PubMed  Google Scholar 

  95. Nakajima M, Yokoi T, Mizutani M, et al. Genetic polymorphism in the 5′-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J Biochem. 1999;125(4):803–8.

    Article  CAS  PubMed  Google Scholar 

  96. Noai M, Soraoka H, Kajiwara A, et al. Cytochrome P450 2C19 polymorphisms and valproic acid-induced weight gain. Acta Neurol Scand. 2016;133(3):216–23.

    Article  CAS  PubMed  Google Scholar 

  97. de Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem. 1994;269(22):15419–22.

    PubMed  Google Scholar 

  98. Kim WJ, Lee JH, Yi J, et al. A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy. Pharmacogenet Genomics. 2010;20(4):249–56.

    CAS  PubMed  Google Scholar 

  99. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci. 2000;97(7):3473–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang Y, Tang L, Pan J, et al. The recessive model of MRP2 G1249A polymorphism decrease the risk of drug-resistant in Asian Epilepsy: a systematic review and meta-analysis. Epilepsy Res. 2015;112:56–63.

    Article  CAS  PubMed  Google Scholar 

  101. Schwarz JR, Grigat G. Phenytoin and carbamazepine: potential- and frequency-dependent block of Na currents in mammalian myelinated nerve fibers. Epilepsia. 1989;30(3):286–94.

    Article  CAS  PubMed  Google Scholar 

  102. Goldin AL. Resurgence of sodium channel research. Annu Rev Physiol. 2001;63:871–94.

    Article  CAS  PubMed  Google Scholar 

  103. Holland KD, Kearney JA, Glauser TA, et al. Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci Lett. 2008;433(1):65–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mao CY, Shi CH, Song B, et al. Genotype-phenotype correlation in a cohort of paroxysmal kinesigenic dyskinesia cases. J Neurol Sci. 2014;340(1–2):91–3.

    Article  CAS  PubMed  Google Scholar 

  105. Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet. 2011;43(12):1252–5.

    Article  CAS  PubMed  Google Scholar 

  106. Kowski AB, Weissinger F, Gaus V, et al. Specific adverse effects of antiepileptic drugs—a true-to-life monotherapy study. Epilepsy Behav. 2016;54:150–7.

    Article  PubMed  Google Scholar 

  107. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364(12):1134–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens–Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013;133(5):1197–204.

    Article  CAS  PubMed  Google Scholar 

  109. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens–Johnson syndrome. Nature. 2004;428(6982):486.

    Article  CAS  PubMed  Google Scholar 

  110. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, et al. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013;149(9):1025–32.

    Article  CAS  PubMed  Google Scholar 

  111. Sun D, Yu CH, Liu ZS, et al. Association of HLA-B*1502 and *1511 allele with antiepileptic drug-induced Stevens–Johnson syndrome in central China. J Huazhong Univ Sci Technol Med Sci. 2014;34(1):146–50.

    Article  CAS  PubMed  Google Scholar 

  112. Chong KW, Chan DW, Cheung YB, et al. Association of carbamazepine-induced severe cutaneous drug reactions and HLA-B*1502 allele status, and dose and treatment duration in paediatric neurology patients in Singapore. Arch Dis Child. 2014;99(6):581–4.

    Article  PubMed  Google Scholar 

  113. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006;16(4):297–306.

    Article  CAS  PubMed  Google Scholar 

  114. Locharernkul C, Loplumlert J, Limotai C, et al. Carbamazepine and phenytoin induced Stevens–Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia. 2008;49(12):2087–91.

    Article  PubMed  Google Scholar 

  115. Then SM, Rani ZZ, Raymond AA, et al. Frequency of the HLA-B*1502 allele contributing to carbamazepine-induced hypersensitivity reactions in a cohort of Malaysian epilepsy patients. Asian Pac J Allergy Immunol. 2011;29(3):290–3.

    CAS  PubMed  Google Scholar 

  116. Kashiwagi M, Aihara M, Takahashi Y, et al. Human leukocyte antigen genotypes in carbamazepine-induced severe cutaneous adverse drug response in Japanese patients. J Dermatol. 2008;35(10):683–5.

    Article  PubMed  Google Scholar 

  117. Alfirevic A, Jorgensen AL, Williamson PR, et al. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics. 2006;7(6):813–8.

    Article  CAS  PubMed  Google Scholar 

  118. Ikeda H, Takahashi Y, Yamazaki E, et al. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions. Epilepsia. 2010;51(2):297–300.

    Article  PubMed  Google Scholar 

  119. Amstutz U, Ross CJ, Castro-Pastrana LI, et al. HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children. Clin Pharmacol Ther. 2013;94(1):142–9.

    Article  CAS  PubMed  Google Scholar 

  120. Apeland T, Mansoor MA, Strandjord RE, et al. Folate, homocysteine and methionine loading in patients on carbamazepine. Acta Neurol Scand. 2001;103(5):294–9.

    Article  CAS  PubMed  Google Scholar 

  121. Kurul S, Unalp A, Yis U. Homocysteine levels in epileptic children receiving antiepileptic drugs. J Child Neurol. 2007;22(12):1389–92.

    Article  PubMed  Google Scholar 

  122. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia. 1999;40(3):345–50.

    Article  CAS  PubMed  Google Scholar 

  123. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–3.

    Article  CAS  PubMed  Google Scholar 

  124. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;324(17):1149–55.

    Article  CAS  PubMed  Google Scholar 

  125. van Beynum IM, Smeitink JA, den Heijer M, et al. Hyperhomocysteinemia: a risk factor for ischemic stroke in children. Circulation. 1999;99(16):2070–2.

    Article  PubMed  Google Scholar 

  126. Vilaseca MA, Monros E, Artuch R, et al. Anti-epileptic drug treatment in children: hyperhomocysteinaemia, B-vitamins and the 677C→T mutation of the methylenetetrahydrofolate reductase gene. Eur J Paediatr Neurol. 2000;4(6):269–77.

    Article  CAS  PubMed  Google Scholar 

  127. Vurucu S, Demirkaya E, Kul M, et al. Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(3):844–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Slobodan M. Jankovic.

Ethics declarations

Funding

This review article was partially supported by Grant No. 175007, given by Serbian Ministry of Education.

Conflict of interest

Natasa Djordjevic, Slobodan Jankovic, and Jasmina Milovanovic declare no conflict of interest in regard to contents of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Djordjevic, N., Jankovic, S.M. & Milovanovic, J.R. Pharmacokinetics and Pharmacogenetics of Carbamazepine in Children. Eur J Drug Metab Pharmacokinet 42, 729–744 (2017). https://doi.org/10.1007/s13318-016-0397-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-016-0397-3

Keywords

Navigation