Effects of UGT1A, CYP2C9/19 and ABAT polymorphisms on plasma concentration of valproic acid in Chinese epilepsy patients
Abstract
Aim: To evaluate the association between genetic polymorphisms and plasma concentration-to-dose ratio of valproic acid (CDRV) in Chinese epileptic patients. Methods: A total of 46 epileptic patients treated with valproic acid therapy were enrolled. 18 SNPs in nine genes related to valproic acid were directly sequenced with Sanger methods. Results: Patients carrying UGT1A6 heterozygous genotypes had significantly lower CDRV than those carrying the wild-type genotypes. In contrast, patients with the homozygote genotypes of CYP2C9 and ABAT had higher CDRV than those with the wild-type genotypes and patients with the heterozygous genotypes of CYP2C19 had higher CDRV. Conclusion: Detection of genetic polymorphism in these genes might facilitate an appropriate dose of valproic acid for epileptic patients. Further studies with larger cohorts are necessary to underpin these observations.
References
- 1. . Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol. 15(2), 210–218 (2016).
- 2. . The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications. Clin. Pharmacokinet. 46(4), 271–279 (2007).
- 3. Valproic acid and epilepsy: from molecular mechanisms to clinical evidences. Curr. Neuropharmacol. 17(10), 926–946 (2019).
- 4. Epigenetic downregulation of Scn3a expression by valproate: a possible role in its anticonvulsant activity. Mol. Neurobiol. 54(4), 2831–2842 (2017).
- 5. Association of CYP2C9 , CYP2A6 , ACSM2A , and CPT1A gene polymorphisms with adverse effects of valproic acid in Chinese patients with epilepsy. Epilepsy Res. 132, 64–69 (2017).
- 6. Functional impact and prevalence of polymorphisms involved in the hepatic glucuronidation of valproic acid. Pharmacogenomics 13(9), 1055–1071 (2012).
- 7. Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy. Braz. J. Med. Biol. Res. 54(9), e11097 (2021).
- 8. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet. Genomics 23(4), 236–241 (2013).
- 9. . Genetic polymorphisms of UDP-glucuronosyltransferases and plasma sodium valproate level. Indian J. Pediatr. 88(8), 747–748 (2021).
- 10. The influence of UGT2B7 genotype on valproic acid pharmacokinetics in Chinese epilepsy patients. Epilepsy Res. 114, 78–80 (2015).
- 11. Testing association of rare genetic variants with resistance to three common antiseizure medications. Epilepsia 61(4), 657–666 (2020).
- 12. The influence of cytochrome oxidase CYP2A6 , CYP2B6 , and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin. Neurol. Neurosurg. 112(4), 320–323 (2010).
- 13. Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients. Eur. J. Clin. Pharmacol. 68(10), 1395–1401 (2012).
- 14. UGT1A6 and UGT2B7 gene polymorphism and its effect in pediatric epileptic patients on sodium valproate monotherapy. Indian J. Pediatr. 88(8), 764–770 (2021).
- 15. UGT1A6- and UGT2B7 -related valproic acid pharmacogenomics according to age groups and total drug concentration levels. Pharmacogenomics 17(8), 827–835 (2016).
- 16. Association of SCN1A , SCN2A , and UGT2B7 polymorphisms with responsiveness to valproic acid in the treatment of epilepsy. Biomed. Res. Int. 2020, 8096235 (2020).
- 17. Early post-traumatic seizures are associated with valproic acid plasma concentrations and UGT1A6/CYP2C9 genetic polymorphisms in patients with severe traumatic brain injury. Scand. J. Trauma Resusc. Emerg. Med. 25(1), 85 (2017).
- 18. Impact of age and genotype on serum concentrations of valproic acid and its hepatotoxic metabolites in Chinese pediatric patients with epilepsy. Ther. Drug Monit. 42(5), 760–765 (2020).
- 19. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol. Ther. 116(3), 496–526 (2007).
- 20. CYP2C9 (*2&*3) and CYP2C19 (*2&*3) polymorphisms among children with nonlesional epilepsy: a single-center study. Acta Neurol. Belg. 121(6), 1623–1631 (2021).
- 21. Associations of CYP2C9 and CYP2A6 polymorphisms with the concentrations of valproate and its hepatotoxin metabolites and valproate-induced hepatotoxicity. Basic Clin. Pharmacol. Toxicol. 121(2), 138–143 (2017).
- 22. CYP2C19 & UGT1A6 genetic polymorphisms and the impact on Valproic acid-induced weight gain in people with epilepsy: prospective genetic association study. Epilepsy Res. 177, 106786 (2021).
- 23. Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia. Sci. Rep. 11(1), 23150 (2021).
- 24. Effect of CYP2C19 , UGT1A8 , and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model. Eur. J. Clin. Pharmacol. 74(8), 1029–1036 (2018).
- 25. Impact of age, gender and CYP2C9/2C19 genotypes on dose-adjusted steady-state serum concentrations of valproic acid-a large-scale study based on naturalistic therapeutic drug monitoring data. Eur. J. Clin. Pharmacol. 72(9), 1099–1104 (2016).
- 26. Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy. Eur. J. Hosp. Pharm. 29(4), 198–201 (2022).
- 27. Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling. Eur. J. Clin. Pharmacol. 65(12), 1187–1193 (2009).
- 28. Influence of UGT2B7 and UGT1A6 polymorphisms on plasma concentration to dose ratio of valproic acid in Chinese epileptic children. Xenobiotica 51(7), 859–864 (2021).
- 29. Influence of uridine diphosphate glucuronosyltransferase 2B7-161C>T polymorphism on the concentration of valproic acid in pediatric epilepsy patients. Ther. Drug Monit. 36(3), 406–409 (2014).
- 30. Polymorphisms of ABAT , SCN2A and ALDH5A1 may affect valproic acid responses in the treatment of epilepsy in Chinese. Pharmacogenomics 17(18), 2007–2014 (2016).
- 31. . The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci. 5(7), 553–564 (2004).
- 32. Effects of UGT2B7 , SCN1A and CYP3A4 on the therapeutic response of sodium valproate treatment in children with generalized seizures. Seizure 58, 96–100 (2018).
- 33. Effects of SCN1A and SCN2A polymorphisms on responsiveness to valproic acid monotherapy in epileptic children. Epilepsy Res. 168, 106485 (2020).
- 34. SCN1A and SCN2A polymorphisms are associated with response to valproic acid in Chinese epilepsy patients. Eur. J. Clin. Pharmacol. 75(5), 655–663 (2019).
- 35. SCN1A IVS5N+5 polymorphism and response to sodium valproate: a multicenter study. Pharmacogenomics 13(13), 1477–1485 (2012).
- 36. Response to sodium channel blocking antiseizure medications and coding polymorphisms of sodium channel genes in Taiwanese epilepsy patients. BMC Neurol. 21(1), 367 (2021).
- 37. . Polymorphisms of the sodium voltage-gated channel, alpha subunit 1 ( SCN1A-A3184G ) gene among children with non-lesional epilepsy: a case-control study. Ital. J. Pediatr. 48(1), 157 (2022).
- 38. Correlations between UGT2B7*2 gene polymorphisms and plasma concentrations of carbamazepine and valproic acid in epilepsy patients. Brain Dev. 40(2), 100–106 (2018).
- 39. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett. 448(1), 105–110 (1999).
- 40. . Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol. Bull. 37(Suppl. 2), 25–42 (2003).
- 41. Association of genetic variants in six candidate genes with valproic acid therapy optimization. Pharmacogenomics 12(8), 1107–1117 (2011).
- 42. Effects of UGT1A6 , UGT2B7 , and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. Drug Metab. Pharmacokinet. 27(5), 536–542 (2012).
- 43. The effect of uridine diphosphate glucuronosyltransferase (UGT)1A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: a pharmacogenetic approach. Mol. Diagn. Ther. 17(5), 319–326 (2013).
- 44. Effects of UGT2B7 genetic polymorphisms on serum concentrations of valproic acid in Chinese children with epilepsy comedicated with lamotrigine. Ther. Drug Monit. 38(3), 343–349 (2016).
- 45. Genetic polymorphisms and valproic acid plasma concentration in children with epilepsy on valproic acid monotherapy. Seizure 51, 22–26 (2017).
- 46. Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin. Pharmacol. Ther. 83(4), 595–600 (2008).
- 47. Prevalence of UGT1A6 polymorphisms in children with epilepsy on valproate monotherapy. Neurol. India 63(1), 35–39 (2015).
- 48. . Association of UGT2B7 and CaMK4 with response of valproic acid in Chinese children with epilepsy. Therapie 75(3), 261–270 (2020).
- 49. . Association of UGT2B7 and UGT1A4 polymorphisms with serum concentration of antiepileptic drugs in children. Med. Sci. Monit. 22, 4107–4113 (2016).
- 50. Clinical significance of CYP2C9 -status guided valproic acid therapy in children. Epilepsia 56(6), 849–855 (2015).
- 51. . Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J. Physiol. 588(Pt 11), 1841–1848 (2010).