Genetic polymorphism and pharmacokinetics/toxicokinetics of carbamazepine: a general review
Abstract
Carbamazepine (CBZ) is a widely used medication in treating epilepsy, bipolar disorder, and neuropathic pain. Its pharmacokinetic profile is highly variable due to slow absorption, extensive metabolism, and auto-induction. Genetic polymorphisms affect transporters and metabolic enzymes, additionally modifying therapeutic response, and lead to nonlinear and unpredictable toxicokinetics in overdose. CBZ is primarily metabolized by cytochrome P450 (CYP) enzymes CYP3A4, CYP3A5, and CYP2C8 to the active metabolite CBZ-10, 11-epoxide (CBZ-E), with subsequent hydrolysis by epoxide hydrolase 1 (EPHX1) and glucuronidation by uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7), with other CYPs additionally contributing to the formation of reactive intermediates and inactive CBZ metabolites. Polymorphisms in genes encoding enzymes (EPHX1, CYP3A4/5, and UGT2B7) and transporters (ABCB1, ABCC2, RALBP1) can affect CBZ and CBZ-E exposure, maintenance dose, and the risk of adverse drug reactions. In overdose cases, CBZ exhibits saturable epoxidation, which leads to the accumulation of the drug and its active metabolite, prolonged elimination, and neurotoxicity, while serum concentrations correlate poorly with clinical findings. Therapeutic monitoring of the drug and its active metabolite in patients’ blood, together with pharmacogenetic testing, could improve both the individualization of therapy and the management of overdose.
References
Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369(9566): 1000–15. DOI: 10.1016/S0140-6736(07)60460-7.
American Society of Health-System Pharmacists. AHFS drug information 2016. 58th ed. Bethesda (US): American Society of Health-System Pharmacists; 2016. p. 3840.
Metcalf CS, Smith MD, Wilcox KS. Pharmacotherapy of the Epilepsies. In: Brunton LL, Knollmann BC, editors. Goodman & Gilman’s The pharmacological basis of therapeutics. 14th ed. NY: McGrawHill; 2023. p. 385–411.
Leikin JB, Paloucek FP. Poisoning and Toxicology Handbook. 4th ed. New York: Informa Healthcare; 2008. p. 167–9.
Doyon S. Anticonvulsants. In: Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE, editors. Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill; 2011. p. 698–710.
Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, et al. Rang & Dale's Pharmacology. 10th ed. London: Elsevier; 2023. p. 3630.
Ragueneau-Majlessi I, Yu J, Isoherranen N. Design and optimization of dosage regimens: pharmacokinetic data. In: Brunton LL, editor. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 14th ed. New York: McGrawHill; 2023. p. 1533–89.
Hundt HK, Aucamp AK, Müller FO. Pharmacokinetic aspects of carbamazepine and its two major metabolites in plasma during overdosage. Hum Toxicol 1983; 2(4): 607–14. DOI: 10.1177/096032718300200405.
Winnicka RI, Łopaciński B, Szymczak WM, Szymańska B. Carbamazepine poisoning: elimination kinetics and quantitative relationship with carbamazepine 10,11-epoxide. J Toxicol Clin Toxicol 2002; 40(6): 759–65. DOI: 10.1081/clt-120015836.
Lukic V, Jankovic SM, Petrovic NZ, Vucinic S, Jovic Stosic J, Djordjevic S, et al. Population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults. Expert Opin Drug Metab Toxicol 2024; 20(8): 817–25. DOI: 10.1080/17425255.2024.2381555.
Methaneethorn J, Lohitnavy M, Leelakanok N. A Systematic Review of Population Pharmacokinetics of Carbamazepine. SRP 2020; 11(10): 653–73. DOI: 10.31838/srp.2020.10.98.
Tolou-Ghamari Z, Zare M, Habibabadi JM, Najafi MR. A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012. J Res Med Sci 2013; 18(Suppl 1): S81–5.
Schwarz A, Strakos C, Weihrich R. A brief review on carbamazepine – history, pharmacological properties and environmental impact. Biochem Insights 2021; 1(4). DOI:10.33552/ICBC.2021.01.000519.
Marvanova M. Pharmacokinetic characteristics of antiepileptic drugs (AEDs). Ment Health Clin 2016; 6(1): 8–20. DOI: 10.9740/mhc.2015.01.008.
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. DOI: 10.5414/cp201517.
Boughrara W, Chentouf A. The ABCB1, ABCC2 and RALBP1 polymorphisms are associated with carbamazepine response in epileptic patient: a systematic review. Acta Neurol Belg 2022; 122(4): 871–80. DOI: 10.1007/s13760-022-01920-5.
Kiełbowski K, Król M, Bakinowska E, Pawlik A. The Role of ABCB1, ABCG2, and SLC Transporters in Pharmacokinetic Parameters of Selected Drugs and Their Involvement in Drug–Drug Interactions. Membranes (Basel) 2024; 14(11): 223. DOI: 10.3390/membranes14110223.
Jemnitz K, Heredi-Szabo K, Janossy J, Ioja E, Vereczkey L, Krajcsi P. ABCC2/Abcc2: a multispecific transporter with dominant excretory functions. Drug Metab Rev 2010; 42(3): 402–36. DOI: 10.3109/03602530903491741.
Djordjevic N, Cukic J, Dragas Milovanovic D, Radovanovic M, Radosavljevic I, Vuckovic Filipovic J, et al. ABCB1 Polymorphism Is Associated with Higher Carbamazepine Clearance in Children. Pediatr Rep 2025; 17(1): 10. DOI: 10.3390/pediatric17010010.
Wang P, Yin T, Ma HY, Liu DQ, Sheng YH, Wang C, 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. DOI: 10.1016/j.eplepsyres.2015.09.001.
Maqbool H, Saleem T, Sheikh N, Asmatullah, Mukhtar M, Javed I, et al. Polymorphism in drug transporter gene ABCB1 is associated with drug resistance in Pakistani epilepsy patients. Epilepsy Res 2021; 178: 106814. DOI: 10.1016/j.eplepsyres.2021.106814.
Fan YX, Zhang Z, Meng JR, Yin SJ, Wang P, Zhou T, et al. Association of ABCB1 polymorphisms with carbamazepine metabolism and resistance in epilepsy: A meta-analysis. Epilepsy Res 2021; 177: 106785. DOI: 10.1016/j.eplepsyres.2021.106785.
Awasthi S, Hallene KL, Fazio V, Singhal SS, Cucullo L, Awasthi YC, et al. RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC Neurosci 2005; 6: 61. DOI: 10.1186/1471-2202-6-61.
Soranzo N, Kelly L, Martinian L, Burley MW, Thom M, Sali A, et al. Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy. Epilepsia 2007; 48(4): 674–83. DOI: 10.1111/j.1528-1167.2007.00926.x.
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. DOI: 10.1358/mf.2008.30.9.1323496.
Thorn CF, Leckband SG, Kelsoe J, Leeder JS, Müller DJ, Klein TE, et al. PharmGKB summary: carbamazepine pathway. Pharmacogenet Genomics 2011; 21(12): 906–10. DOI: 10.1097/FPC.0b013e328348c6f2.
Kang P, Liao M, Wester MR, Leeder JS, Pearce RE, Correia MA. 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. DOI: 10.1124/dmd.107.016501.
ClinPGx. Carbamazepine pathway, pharmacokinetics – pathway PA165817070 [Internet]. Leuven (BE): ClinPharGenomics; 2011 [cited 2025 Nov 11; accessed 2026 Jan 21]. Available from: https://www.clinpgx.org/pathway/PA165817070/overview
Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia 2013; 54(1): 11–27. DOI: 10.1111/j.1528-1167.2012.03671.x.
Djordjevic N, Milovanovic DD, Radovanovic M, Radosavljevic I, Obradovic S, Jakovljevic M, et al. CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy. Eur J Clin Pharmacol 2016; 72(4): 439–45. DOI: 10.1007/s00228-015-2006-9.
Alvarado AT, Muñoz AM, Varela N, Sullón-Dextre L, Pineda M, Bolarte-Arteaga M, et al. Pharmacogenetic variants of CYP2C9 and CYP2C19 associated with adverse reactions induced by antiepileptic drugs used in Peru. Pharmacia 2023; 70(3): 603–18. DOI: 10.3897/pharmacia.70.e109011.
Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, et al. An evidence-based framework for evaluating pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2021; 110(3): 563–72. DOI: 10.1002/cpt.2350.
Iannaccone T, Sellitto C, Manzo V, Colucci F, Giudice V, Stefanelli B, et al. Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters. Pharmaceuticals (Basel) 2021; 14(3): 204. DOI: 10.3390/ph14030204.
Makmor-Bakry M, Sills GJ, Hitiris N, Butler E, Wilson EA, Brodie MJ. Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing. Clin Neuropharmacol 2009; 32(4): 205–12. DOI: 10.1097/WNF.0b013e318187972a.
He XJ, Jian LY, He XL, Tang M, Wu Y, Xu YY, et al. Association of ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms with the risk of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Chinese Han patients with epilepsy. Epilepsia 2014; 55(8): 1301–6. DOI: 10.1111/epi.12655.
Hung CC, Chang WL, Ho JL, Tai JJ, Hsieh TJ, Huang HC, et al. Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization. Pharmacogenomics 2012; 13(2): 159–69. DOI: 10.2217/pgs.11.141.
Yip VLM, Pertinez H, Meng X, Maggs JL, Carr DF, Park BK, et al. Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine. Br J Clin Pharmacol 2021; 87(6): 2572–88. DOI: 10.1111/bcp.14667.
Saiz-Rodríguez M, Almenara S, Navares-Gómez M, Ochoa D, Román M, Zubiaur P, et al. Effect of the Most Relevant CYP3A4 and CYP3A5 Polymorphisms on the Pharmacokinetic Parameters of 10 CYP3A Substrates. Biomedicines 2020; 8(4): 94. DOI: 10.3390/biomedicines8040094.
Zhao W, Meng H. Effects of genetic polymorphism of drug-metabolizing enzymes on the plasma concentrations of antiepileptic drugs in Chinese population. Bioengineered 2022; 13(3): 7709–45. DOI: 10.1080/21655979.2022.2036916.
Djordjevic N, Jankovic SM, Milovanovic JR. Pharmacokinetics and Pharmacogenetics of Carbamazepine in Children. Eur J Drug Metab Pharmacokinet 2017; 42(5): 729–44. DOI: 10.1007/s13318-016-0397-3.
Zhao GX, Zhang Z, Cai WK, Shen ML, Wang P, He GH. Associations between CYP3A4, CYP3A5 and SCN1A polymorphisms and carbamazepine metabolism in epilepsy: A meta-analysis. Epilepsy Res 2021; 173: 106615. DOI: 10.1016/j.eplepsyres.2021.106615.
Jamil A, Faisal MS, Zaman G, Khan M. Decoding the genome: CYP3A5 rs15524 polymorphism and how it affects plasma carbamazepine levels in patients with epilepsy in Khyber Pakhtunkhwa. Afr J Biomed Res 2024; 31(1): 1187–94.
Ganesapandian M, Ramasamy K, Adithan S, Narayan SK. Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on dose-adjusted plasma levels of carbamazepine in epileptic patients in South Indian population. Indian J Pharmacol 2019; 51(6): 384–8. DOI: 10.4103/ijp.IJP_122_19.
Seo T, Nakada N, Ueda N, Hagiwara T, Hashimoto N, Nakagawa K, et al. Effect of CYP3A5*3 on carbamazepine pharmacokinetics in Japanese patients with epilepsy. Clin Pharmacol Ther 2006; 79(5): 509–10. DOI: 10.1016/j.clpt.2006.02.009.
Ragia G, Dahl ML, Manolopoulos VG. Influence of CYP3A5 polymorphism on the pharmacokinetics of psychiatric drugs. Curr Drug Metab 2016; 17(3): 227–36. DOI: 10.2174/1389200217666151210125831.
Miyata-Nozaka Y, Zain SM, Taguchi M, Shigeyama M, Isobe T, Hanioka N. Carbamazepine 10,11-epoxidation in human liver microsomes: influence of the CYP3A5*3 polymorphism. Pharmazie 2017; 72(12): 747–50. DOI: 10.1691/ph.2017.7754.
Lu Q, Huang YT, Shu Y, Xu P, Xiang DX, Qu Q, et al. Effects of CYP3A5 and UGT2B7 variants on steady-state carbamazepine concentrations in Chinese epileptic patients. Medicine (Baltimore) 2018; 97(30): e11662. DOI: 10.1097/MD.0000000000011662.
Saleh Faisal M, Jamil A, Ali N, Alshahrani AM, Almarshad F. Distribution pattern of UGT1A6 and UGT2B7 gene polymorphism and its impact on the pharmacokinetics of valproic acid and carbamazepine: Prospective genetic association study conducted in Pakistani patients with epilepsy. Gene 2024; 892: 147886. DOI: 10.1016/j.gene.2023.147886.
Milovanovic J, Jankovic S. Population pharmacokinetics. Vojnosanit Pregl 2005; 62(11): 847–50. (Serbian) DOI:10.2298/VSP0511847M.
Kanojia N, Kukal S, Machahary N, Bora S, Srivastava A, Paul PR, et al. Antiepileptic drugs carbamazepine and valproic acid mediate transcriptional activation of CYP1A1 via aryl hydrocarbon receptor and regulation of estrogen metabolism. J Steroid Biochem Mol Biol 2025; 248: 106699. DOI: 10.1016/j.jsbmb.2025.106699.
Zhang ML, Chen XL, Bai ZF, Zhao X, Li WX, Wang XY, et al. ABCB1 c.3435C > T and EPHX1 c.416A > G polymorphisms influence plasma carbamazepine concentration, metabolism, and pharmacoresistance in epileptic patients. Gene 2021; 805: 145907. DOI: 10.1016/j.gene.2021.145907.
Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit 2018; 40(5): 526–48. DOI: 10.1097/FTD.0000000000000546.
Đordević S, Kilibarda V, Stojanović T. Determination of carbamazepine in serum and saliva samples by high performance liquid chromatography with ultraviolet detection. Vojnosanit Pregl 2009; 66(5): 347–52. DOI: 10.2298/vsp0905347d.
Hojer J, Malmlund HO, Berg A. Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine alone. J Toxicol Clin Toxicol 1993; 31(3): 449–58. DOI: 10.3109/15563659309000412.
Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care 2012; 16(4): R136. DOI: 10.1186/cc11441.
Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet 1996; 31(3): 198–214. DOI: 10.2165/00003088-199631030-00004.
Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. The Lancet Neurol 2003; 2(6): 347–56. DOI: 10.1016/s1474-4422(03)00483-6.
Belhekar MN, Vinayak A, More S, Ambre S, Khimsuriya H. A randomised controlled trial to evaluate genotyping and therapeutic drug monitoring vs only therapeutic drug monitoring as a strategy for risk minimisation in epileptic patients on carbamazepine therapy. Recent Trends Pharmacol 2025; 3(1): 27–35. DOI:10.62425/rtpharma.1614127.
Jaramillo NM, Galindo IF, Vázquez AO, Cook HJ, LLerena A, López ML. Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response. Drug Metabol Drug Interact 2014; 29(2): 67–79. DOI: 10.1515/dmdi-2013-0046.
Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev 2020; 72(3): 606–38. DOI: 10.1124/pr.120.019539.
Puranik YG, Birnbaum AK, Marino SE, Ahmed G, Cloyd JC, Remmel RP, et al. Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics 2013; 14(1): 35–45. DOI: 10.2217/pgs.12.180.
Fuhr LM, Marok FZ, Hanke N, Selzer D, Lehr T. Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug-Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach. Pharmaceutics 2021; 13(2): 270. DOI: 10.3390/pharmaceutics13020270.
Russell JL, Spiller HA, Baker DD. Markedly Elevated Carbamazepine-10,11-epoxide/Carbamazepine Ratio in a Fatal Carbamazepine Ingestion. Case Rep Med 2015; 2015: 369707. DOI: 10.1155/2015/369707.
Maan JS, Duong TvH, Saadabadi A. Carbamazepine [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2025 Feb 14; accessed 2026 Jan 21]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482455/
Wang L, Wang Y, Zhang RY, Wang Y, Liang W, Li TG. Management of acute carbamazepine poisoning: A narrative review. World J Psychiatry 2023; 13(11): 816–30. DOI: 10.5498/wjp.v13.i11.816.
Al Khalili Y, Sekhon S, Jain S. Carbamazepine toxicity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Feb 14; accessed 2026 Jan 21]. Available from: https://pubmed.ncbi.nlm.nih.gov/29939629/
Djordjević S, Kilibarda V, Vucinić S, Stojanović T, Antonijević B. Toxicokinetics and correlation of carbamazepine salivary and serum concentrations in acute poisonings. Vojnosanit Pregl 2012; 69(5): 389–93. DOI: 10.2298/VSP1205389D.
Durelli L, Massazza U, Cavallo R. Carbamazepine toxicity and poisoning. Incidence, clinical features and management. Med Toxicol Adverse Drug Exp 1989; 4(2): 95–107. DOI: 10.1007/BF03259906.
Patel VH, Schindlbeck MA, Bryant SM. Delayed elevation in carbamazepine concentrations after overdose: a retrospective poison center study. Am J Ther 2013; 20(6): 602–6. DOI: 10.1097/MJT.0b013e3182258e51.
Rosenberg J, Benowitz NL, Pond S. Pharmacokinetics of drug overdose. Clin Pharmacokinet 1981; 6(3): 161–92. DOI: 10.2165/00003088-198106030-00001.
Graudins A, Peden G, Dowsett RP. Massive overdose with controlled-release carbamazepine resulting in delayed peak serum concentrations and life-threatening toxicity. Emerg Med (Fremantle) 2002; 14(1): 89–94. DOI: 10.1046/j.1442-2026.2002.00290.x.
Roberts DM, Buckley NA. Pharmacokinetic considerations in clinical toxicology: clinical applications. Clin Pharmacokinet 2007; 46(11): 897–939. DOI: 10.2165/00003088-200746110-00001.
Perez A, Wiley JF. Pediatric carbamazepine suspension overdose-clinical manifestations and toxicokinetics. Pediatr Emerg Care 2005; 21(4): 252–4. DOI: 10.1097/01.pec.0000161471.57959.28.
Abdel-Ghaffar Abdel-Dayem RS, Elshama SS, Maklad AI, Elmansy AM. Assessment of the pattern, severity, and outcomes of acute mood stabilizer drug poisoning. Toxicol Res (Camb) 2024; 13(6): tfae193. DOI: 10.1093/toxres/tfae193.
Vree TB, Janssen TJ, Hekster YA, Termond EF, van de Dries AC, Wijnands WJ. Clinical pharmacokinetics of carbamazepine and its epoxy and hydroxy metabolites in humans after an overdose. Ther Drug Monit 1986; 8(3): 297–304. DOI: 10.1097/00007691-198609000-00011.
Waseem M. Carbamazepine toxicity: practice essentials [Internet]. Medscape; 2025 [cited 2025 Nov 14; accessed 2026 Jan 21]. Available from: https://emedicine.medscape.com/article/813654-overview
Staniszewska A, Burda P, Waldman W, Anand JS. Correlation between carbamazepine serum level and clinical condition of acute poisoned patient. Przegl Lek 2009; 66(6): 279–81. (Polish)
Montgomery VL, Richman BJ, Goldsmith LJ, Rodgers GC Jr. Severity and carbamazepine level at time of initial poison center contact correlate with outcome in carbamazepine poisoning. J Toxicol Clin Toxicol 1995; 33(4): 311–23. DOI: 10.3109/15563659509028916.