Pharmacogenetics-Informed Pharmacometabolomics as an Innovative Approach to Assessing the Safety and Risk of Pharmacotherapy with Valproic Acid

Scientific relevance. Valproic acid (VPA) is a psychotropic medicinal product, which may be associated with serious adverse drug reactions (ADRs). While pharmacogenetics and pharmacometabolomics can significantly affect the safety of valproates, there are no unified approaches to predicting, preventing, and correcting VPA-induced ADRs.

Aim. This study aimed to collate the results of national and international studies on toxic VPA metabolites and to develop a novel personalised approach to assessing the safety and risks of valproate therapy in real-world clinical practice.

Discussion. This study analysed national and international publications reflecting the results of preclinical and clinical studies on toxic VPA metabolites submitted to e-Library, PubMed, Scopus, and Google Scholar in 2012–2022. The inclusion criteria were full-text original articles, systematic reviews, meta-analyses, Cochrane reviews, and clinical cases in Russian or English. According to the analysis results, VPA has 20 studied toxic metabolites, which result from hepatic VPA metabolism involving P-oxidation, acetylation (β-oxidation), and glucuronidation enzymes. The functional activity of these enzymes is genetically determined and associated with heterozygous or homozygous carriage of non-functional/low-function single-nucleotide variant alleles in genes encoding these enzymes. The safety of VPA and its compounds can be improved by transferring the results of preclinical and clinical studies into real-world clinical practice using pharmacogenetics-informed pharmacometabolomics. Pharmacogenetics-informed pharmacometabolomics is a novel and personalised approach that helps, based on pharmacogenetic profiling, identify patients at high risk of VPA-induced ADRs, individually select starting and target doses of VPA and its compounds, determine the timing and frequency for therapeutic drug monitoring and monitoring toxic VPA metabolites in biological fluids (blood, saliva, and urine), and select a strategy for the prevention and correction of VPA-induced ADRs, taking into account patients’ individual pharmacometabolic profiles.

Conclusions. The quality of medical care for patients with neurological diseases and mental disorders will improve with proper monitoring of VPA-induced ADRs by all entities involved in the medicinal product life cycle; active involvement of neurologists and psychiatrists in the prediction, prevention, and monitoring of the safety of valproate treatment; and inclusion of specific sections on practical pharmacogenetics-informed pharmacometabolomics and pharmacovigilance in the professional training curricula for neurologists and psychiatrists.

1. Bochanova EN, Shnayder NA, Zyryanov SK, Dmitrenko DV, Zhuravlev DA, Nozdrachev KG, et al. Consumption of antiepileptic drugs in the outpatient practice. Clinical Pharmacology and Therapy. 2016;25(3):90–2 (In Russ.). EDN: VXESIF

2. Shnaider NA, Dmitrenko DV. Chronic valproic acid intoxication in epileptology: diagnosis and treatment. Neurology, Neuropsychiatry, Psychosomatics. 2016;8(2):94–9 (In Russ.). https://doi.org/10.14412/2074-2711-2016-2-94-99

3. Naumova GI, Vlasov PN, Prusakova OI, Usoltseva AA, Shnayder NA, Dmitrenko DV. Withdrawal of valproic acid during pregnancy in women with epilepsy. Neurology, Neuropsychiatry, Psychosomatics. 2023;15(2):27–33 (In Russ.). https://doi.org/10.14412/2074-2711-2023-2-27-33

4. Avakyan GN, Blinov DV, Avakyan GG, Akarachkova ES, Burd SG, Vlasov PN, et al. Restrictions on the use of valproate in female patients of reproductive age: the updated recommendations based on recent clinical data. Epilepsy and Paroxysmal Conditions. 2019;11(2):110–23 (In Russ.). https://doi.org/10.17749/2077-8333.2019.11.2.110-123

5. Bochanova EN, Gusev SD, Dmitrenko DV, Shnayder NA, Nasyrova RF. A protocol for personalized valproic acid therapy for epilepsy. Doctor.Ru. 2019;(6):6–11 (In Russ.). https://doi.org/10.31550/1727-2378-2019-161-6-6-11

6. Nasyrova RF, Neznanov NG. Clinical psychopharmacogenetics. St. Petersburg: DEAN; 2020 (In Russ.). EDN: QCOSIL

7. Shnayder NA, Grechkina VV, Khasanova AK, Bochanova EN, Dontceva EA, Petrova MM, et al. Therapeutic and toxic effects of valproic acid metabolites. Metabolites. 2023;13(1):134. https://doi.org/10.3390/metabo13010134

8. Shnayder NA, Grechkina VV, Trefilova VV, Efremov IS, Dontceva EA, Narodova EA, et al. Valproate-induced metabolic syndrome. Biomedicines. 2023;11(5):1499. https://doi.org/10.3390/biomedicines11051499

9. Aluru N, Deak KL, Jenny MJ, Hahn ME. Developmental exposure to valproic acid alters the expression of microRNAs involved in neurodevelopment in zebrafish. Neurotoxicol Teratol. 2013;40:46–58. https://doi.org/10.1016/j.ntt.2013.10.001

10. Hara Y, Ago Y, Takano E, Hasebe S, Nakazawa T, Hashimoto H, et al. Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain. Mol Autism. 2017;8:33. https://doi.org/10.1186/s13229-017-0149-5

11. Ji Y, Hebbring S, Zhu, H, Jenkins GD, Biernacka J, Snyder K, et al. Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response bio markers in depression: pharmacometabolo micsinformed pharmacogenomics. Clin Pharmacol Ther. 2011;89(1):97–104. https://doi.org/10.1038/clpt.2010.250

12. Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2013;23(4):236–41. https://doi.org/10.1097/FPC.0b013e32835ea0b2

13. Dmitrenko DV, Schnaider NA, Egorova AT, Bochanova EN, Veselova OF, Kantimirova EA, et al. Epilepsy and pregnancy. Moscow: Medika; 2014 (In Russ.). EDN: UCPBJR

14. Vlasov PN, Karlov VA, Petrukhin VA. Epilepsy and pregnancy: current therapeutic tactics. Neurology, Neuropsychiatry, Psychosomatics. 2013;(1):13–7 (In Russ.). EDN: RBTDHH

15. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696–703. https://doi.org/10.1001/jama.2013.2270

16. Sychev DA., Shuev GN, Torbenkov ES, Adriyanova MА. Personalized medicine: clinical pharmacologist’s opinion. Consilium Medicum. 2017;19(1):61–8 (In Russ.). EDN: YSQFFL

17. Siemes H, Nau H, Schultze K, Wittfoht W, Drews E, Penzien J, Seidel U. Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity. Epilepsia. 1993;34(2):332–46. https://doi.org/10.1111/j.1528-1157.1993.tb02419.x

18. Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2013;23(4):236–41. https://doi.org/10.1097/fpc.0b013e32835ea0b2

19. Wishart DS, Guo A, Oler E, Wang F, Anjum A, Peters H, et al. HMDB 5.0: The Human Metabolome Database for 2022. Nucleic Acids Res. 2022;50(D1):D622–31. https://doi.org/10.1093/nar/gkab1062

20. Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010:479364. https://doi.org/10.1155/2010/479364

21. Tang W, Abbott FS. Bioactivation of a toxic metabolite of valproic acid, (E)-2-propyl-2,4-pentadienoic acid, via glucuronidation. LC/MS/MS characterization of the GSH-glucuronide diconjugates. Chem Res Toxicol. 1996;9(2):517–26. https://doi.org/10.1021/tx950120y

22. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47(2);101–11. https://doi.org/10.1080/15563650902752376

23. Millington DS, Bohan TP, Roe CR, Yergey AL, Liberato DJ. Valproylcarnitine: a novel drug metabolite identified by fast atom bombardment and thermo spray liquid chromatography-mass spectrometry. Clin Chim Acta. 1985;145(1):69–76. https://doi.org/10.1016/0009-8981(85)90020-8

24. Torres S, Baulies A, Insausti-Urkia N, Alarcón-Vila C, Fucho R, Solsona-Vilarrasa E, et al. Endoplasmic reticulum stress-induced upregulation of STARD1 promotes acetaminophen-induced acute liver failure. Gastroenterology. 2019;157(2):552–68. https://doi.org/10.1053/j.gastro.2019.04.023

25. Kudin AP, Mawasi H, Eisenkraft A, Elger CE, Bialer M, Kunz WS. Mitochondrial liver toxicity of valproic acid and its acid derivatives is related to inhibition of α-lipoamide dehydrogenase. Int J Mol Sci. 2017;18(9):1912. https://doi.org/10.3390/ijms18091912

26. Kim B, Kim CY, Lee MJ, Joo YH. Preliminary evidence on the association between XBP1-116C/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders. Psychiatry Res. 2009;168(3):209–12. https://doi.org/10.1016/j.psychres.2008.05.010

27. Dmitrenko DV, Shnaider NA, Strotskaya IG, Kichkaylo AS, Zobova SN. Mechanisms of valproate-induced teratogenesis. Neurology, Neuropsychiatry, Psychosomatics. 2017;9(1S):89–96 (In Russ.). https://doi.org/10.14412/2074-2711-2017-1S-89-96

28. Doré M, San Juan AE, Frenette AJ, Williamson D. Clinical importance of monitoring unbound valproic acid concentration in patients with hypoalbuminemia. Pharmacotherapy. 2017;37(8):900–7. https://doi.org/10.1002/phar.1965

29. Patel AR, Nagalli S. Valproate toxicity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. PMID: 32809733

30. Li X, Zhu Y, He H, Lou L, Ye W, Chen Y, Wang J. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells. Biochem Biophys Res Commun. 2013;436(2):259–64. https://doi.org/10.1016/j.bbrc.2013.05.088

31. Vaiman EE, Shnaider NA, Neznanov NG, Nasyrova RF. Drug-induced parkinsonism. Social and Clinical Psychiatry. 2021;31(1):96–103 (In Russ.). EDN: MWEAHI

32. Carriere CH, Kang NH, Niles LP. Neuroprotection by valproic acid in an intrastriatal rotenone model of Parkinson’s disease. Neuroscience. 2014;267:114–21. https://doi.org/10.1016/j.neuroscience.2014.02.028

33. Mahmoud F, Tampi RR. Valproic acid-induced parkinsonism in the elderly: a comprehensive review of the literature. Am J Geriatr Pharmacother. 2011;9(6):405–12. https://doi.org/10.1016/j.amjopharm.2011.09.002

34. Neavin D, Kaddurah-Daouk R, Weinshilboum R. Pharmacometabolomics informs pharmacogenomics. Metabolomics. 2016;12(7):121. https://doi.org/10.1007/s11306-016-1066-x

35. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med. 2011;364(12):1144–53. https://doi.org/10.1056/nejmra1010600

36. Kaddurah-Daouk R, Weinshilboum RM. Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology. Clin Pharmacol Ther. 2014;95(2):154–67. https://doi.org/10.1038/clpt.2013.217

37. Nasyrova RF, Sivakova NA, Lipatova LV, Sosina KA, Drokov AP, Shnayder NA. Biological markers of the antiepileptic drug efficacy and safety: pharmacogenetics and pharmacokinetics. Siberian Medical Review. 2017;(1):17–25 (In Russ.). https://doi.org/10.20333/2500136-2017-1-17-25

38. Okumura A, Takagi M, Numoto S, Iwayama H, Azuma Y, Kurahashi H. Effects of L-carnitine supplementation in patients with childhood-onset epilepsy prescribed valproate. Epilepsy Behav. 2021;122:108220. https://doi.org/10.1016/j.yebeh.2021.108220

39. Guo HL, Jing X, Sun JY, Hu YH, Xu ZJ, Ni MM, et al. Valproic acid and the liver injury in patients with epilepsy: an update. Curr Pharm Des. 2019;25(3):343–51. https://doi.org/10.2174/1381612825666190329145428

40. Yoon S, Lee H, Ji SC, Yoon SH, Cho JY, Chung JY. Pharmacokinetics and pharmacodynamics of ursodeoxycholic acid in an overweight population with abnormal liver function. Clin Pharmacol Drug Dev. 2021;10(1):68–77. https://doi.org/10.1002/cpdd.790

41. Asgarshirazi M, Shariat M, Dalili H, Keihanidoost Z. Ursodeoxycholic acid can improve liver transaminase quantities in children with anticonvulsant drugs hepatotoxicity: a pilot study. Acta Med Iran. 2015;53(6):351–5. PMID: 26069172

42. Plummer S, Beaumont B, Elcombe M, Wallace S, Wright J, Mcinnes EF, et al. Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues. Toxicol Rep. 2020;8:155–61. https://doi.org/10.1016/j.toxrep.2020.12.019

43. Tutty MA, Movia D, Prina-Mello A. Three-dimensional (3D) liver cell models — a tool for bridging the gap between animal studies and clinical trials when screening liver accumulation and toxicity of nano biomaterials. Drug Deliv Transl Res. 2022;12(9):2048–74. https://doi.org/10.1007/s13346-022-01147-0

44. Bochanova EN, Shnayder NA, Dmitrenko DV, Artyukhov IP, Gusev SD, Yurjieva EA, Shilkina OS. Process of personalized prescription of valproic acid as the main element of the management of epilepsy. Int J Biomed. 2018;(8):26–32. https://doi.org/10.21103/Article8(1)_OA3

45. Neznanov NG. A paradigm shift to treat psychoneurological disorders. Personalized Psychiatry and Neurology. 2021;1(1):1–2. EDN: ZSRZDY

46. Sychev DA, Chernyaeva MS, Ostroumova OD. Genetic risk factors for adverse drug reactions. Safety and Risk of Pharmacotherapy. 2022;10(1):48–64 (In Russ.). https://doi.org/10.30895/2312-7821-2022-10-1-48-64