{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:59:07Z","timestamp":1791446347522,"version":"4.3.3"},"reference-count":143,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T00:00:00Z","timestamp":1673827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Valproic acid (VPA) and its salts are psychotropic drugs that are widely used in neurological diseases (epilepsy, neuropathic pain, migraine, etc.) and psychiatric disorders (schizophrenia, bipolar affective disorder, addiction diseases, etc.). In addition, the indications for the appointment of valproate have been expanding in recent years in connection with the study of new mechanisms of action of therapeutic and toxic metabolites of VPA in the human body. Thus, VPA is considered a component of disease-modifying therapy for multiple tumors, neurodegenerative diseases (Huntington\u2019s disease, Parkinson\u2019s disease, Duchenne progressive dystrophy, etc.), and human immunodeficiency syndrome. The metabolism of VPA is complex and continues to be studied. Known pathways of VPA metabolism include: \u03b2-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation. The complex metabolism of VPA explains the diversity of its active and inactive metabolites, which have therapeutic, neutral, or toxic effects. It is known that some active metabolites of VPA may have a stronger clinical effect than VPA itself. These reasons explain the relevance of this narrative review, which summarizes the results of studies of blood (serum, plasma) and urinary metabolites of VPA from the standpoint of the pharmacogenomics and pharmacometabolomics. In addition, a new personalized approach to assessing the cumulative risk of developing VPA-induced adverse reactions is presented and ways for their correction are proposed depending on the patient\u2019s pharmacogenetic profile and the level of therapeutic and toxic VPA metabolites in the human body fluids (blood, urine).<\/jats:p>","DOI":"10.3390\/metabo13010134","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T01:41:20Z","timestamp":1673919680000},"page":"134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Therapeutic and Toxic Effects of Valproic Acid Metabolites"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2840-837X","authenticated-orcid":false,"given":"Natalia A.","family":"Shnayder","sequence":"first","affiliation":[{"name":"Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia"},{"name":"Shared Core Facilities \u201cMolecular and Cell Technologies\u201d, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8279-4198","authenticated-orcid":false,"given":"Violetta V.","family":"Grechkina","sequence":"additional","affiliation":[{"name":"Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5391-0786","authenticated-orcid":false,"given":"Aiperi K.","family":"Khasanova","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Russian Medical Academy for Continual Professional Education, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena N.","family":"Bochanova","sequence":"additional","affiliation":[{"name":"Shared Core Facilities \u201cMolecular and Cell Technologies\u201d, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgenia A.","family":"Dontceva","sequence":"additional","affiliation":[{"name":"Shared Core Facilities \u201cMolecular and Cell Technologies\u201d, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina M.","family":"Petrova","sequence":"additional","affiliation":[{"name":"Shared Core Facilities \u201cMolecular and Cell Technologies\u201d, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azat R.","family":"Asadullin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Addiction, Bashkir State Medical University, 45000 Ufa, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German A.","family":"Shipulin","sequence":"additional","affiliation":[{"name":"Centre for Strategic Planning and Management of Biomedical Health Risks, 119121 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuanysh S.","family":"Altynbekov","sequence":"additional","affiliation":[{"name":"Republican Scientific and Practical Center of Mental Health, Almaty 050022, Kazakhstan"},{"name":"Department of Psychiatry and Narcology, S.D. Asfendiarov Kazakh National Medical University, Almaty 050022, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3643-982X","authenticated-orcid":false,"given":"Mustafa","family":"Al-Zamil","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, Faculty of Continuing Medical Education, Peoples\u2019 Friendship University of Russia, 11798 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1874-9434","authenticated-orcid":false,"given":"Regina F.","family":"Nasyrova","sequence":"additional","affiliation":[{"name":"Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1080\/01612840.2022.2122431","article-title":"Versatile Valproic Acid","volume":"43","author":"Woolley","year":"2022","journal-title":"Issues Ment. Health Nurs."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"926","DOI":"10.2174\/1570159X17666181227165722","article-title":"Valproic acid and epilepsy: From molecular mechanisms to clinical evidences","volume":"17","author":"Romoli","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/j.1365-2710.2005.00671.x","article-title":"Valproate: A simple chemical with so much to offer","volume":"30","author":"Peterson","year":"2005","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_4","first-page":"CD003196","article-title":"Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder","volume":"3","author":"Macritchie","year":"2001","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Iannaccone, T., Sellitto, C., Manzo, V., Colucci, F., Giudice, V., Stefanelli, B., Iuliano, A., Corrivetti, G., and Filippelli, A. (2021). Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030204"},{"key":"ref_6","first-page":"CD010611","article-title":"Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults","volume":"6","author":"Linde","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107332","DOI":"10.1016\/j.intimp.2020.107332","article-title":"Valproic acid mitigates spinal nerve ligation-induced neuropathic pain in rats by modulating microglial function and inhibiting neuroinflammatory response","volume":"92","author":"Guo","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, Y., Xia, J., Helfer, B., Li, C., and Leucht, S. (2016). Valproate for schizophrenia. Cochrane Database Syst. Rev., 11.","DOI":"10.1002\/14651858.CD004028.pub4"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"213","DOI":"10.3109\/00048678009159381","article-title":"Sodium valproate in the treatment of the alcohol withdrawal syndrome","volume":"14","author":"Lambie","year":"1980","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6321","DOI":"10.1158\/0008-5472.CAN-04-4252","article-title":"Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate","volume":"65","author":"Armeanu","year":"2005","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kristensen, \u00d8., L\u00f8landsmo, T., Isaksen, A., Vederhus, J.K., and Clausen, T. (2006). Treatment of polydrug-using opiate dependents during withdrawal: Towards a standardisation of treatment. BMC Psychiatry, 6.","DOI":"10.1186\/1471-244X-6-54"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1111\/add.13297","article-title":"Should compulsive sexual behavior be considered an addiction?","volume":"111","author":"Kraus","year":"2016","journal-title":"Addiction"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"479364","DOI":"10.1155\/2010\/479364","article-title":"Molecular and therapeutic potential and toxicity of valproic acid","volume":"2010","author":"Chateauvieux","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0140-6736(05)67098-5","article-title":"Depletion of latent HIV-1 infection in vivo: A proof-of-concept study","volume":"366","author":"Lehrman","year":"2005","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"999","DOI":"10.2353\/ajpath.2009.080537","article-title":"Valproic acid activates the PI3K\/Akt\/mTOR pathway in muscle and ameliorates pathology in a mouse model of Duchenne muscular dystrophy","volume":"174","author":"Gurpur","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ctrv.2007.11.003","article-title":"Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors","volume":"34","author":"Candelaria","year":"2008","journal-title":"Cancer Treat. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/jhg.2017.91","article-title":"The pharmacogenomics of valproic acid","volume":"62","author":"Zhu","year":"2017","journal-title":"J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"695","DOI":"10.2165\/00023210-200216100-00004","article-title":"Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience","volume":"16","author":"Perucca","year":"2002","journal-title":"CNS Drugs."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s10545-008-0841-x","article-title":"Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review","volume":"31","author":"Silva","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.freeradbiomed.2017.10.298","article-title":"285\u2014VPA Inhibits P19 Neural Differentiation through Redox Dysregulation and Oxidative Stress","volume":"112","author":"Benjamin","year":"2017","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_21","first-page":"7","article-title":"Effect of valproic acid on metabolic status and endocrine system in pediatric patients with epilepsy: Systematic literature review","volume":"4","author":"Sepahi","year":"2017","journal-title":"Rev. Clin. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.bcp.2010.11.011","article-title":"Valproic acid perturbs hematopoietic homeostasis by inhibition of erythroid differentiation and activation of the myelo-monocytic pathway","volume":"81","author":"Chateauvieux","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1021\/tx950120y","article-title":"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","volume":"9","author":"Tang","year":"1996","journal-title":"Chem. Res. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kudin, A.P., Mawasi, H., Eisenkraft, A., Elger, C.E., Bialer, M., and Kunz, W.S. (2017). Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of \u03b1-Lipoamide Dehydrogenase. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091912"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s12031-008-9056-8","article-title":"Neuronal peroxisome proliferator-activated receptor gamma signaling: Regulation by mood-stabilizer valproate","volume":"35","author":"Lan","year":"2008","journal-title":"J. Mol. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.bbrc.2008.12.132","article-title":"HDAC3 influences phosphorylation of STAT3 at serine 727 by interacting with PP2A","volume":"379","author":"Togi","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4595","DOI":"10.1007\/s11033-014-3330-3","article-title":"Valproic acid inhibits the proliferation of SHSY5Y neuroblastoma cancer cells by downregulating URG4\/URGCP and CCND1 gene expression","volume":"41","author":"Dodurga","year":"2014","journal-title":"Mol. Biol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9636897211027524","DOI":"10.1177\/09636897211027524","article-title":"Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering Pyruvate Kinase M2 Isoform Mediated Warburg Effect","volume":"30","author":"Li","year":"2021","journal-title":"Cell Transplant."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.fct.2019.05.019","article-title":"Human CYP3A4-mediated toxification of the pyrrolizidine alkaloid lasiocarpine","volume":"130","author":"Ebmeyer","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113890","DOI":"10.1016\/j.ejmech.2021.113890","article-title":"Reactive metabolites of the anticonvulsant drugs and approaches to minimize the adverse drug reaction","volume":"226","author":"Pal","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1124\/dmd.114.059352","article-title":"Evaluation of in situ generated valproyl 1-O-\u03b2-acyl glucuronide in valproic acid toxicity in sandwich-cultured rat hepatocytes","volume":"42","author":"Surendradoss","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1021\/acs.chemrestox.0c00081","article-title":"Structure-Based Reactivity Profiles of Reactive Metabolites with Glutathione","volume":"33","author":"Liu","year":"2020","journal-title":"Chem. Res. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00775-021-01879-3","article-title":"Bis(triazinyl)pyridine complexes of Pt(II) and Pd(II): Studies of the nucleophilic substitution reactions, DNA\/HSA interactions, molecular docking and biological activity","volume":"26","author":"Scheurer","year":"2021","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/wrna.79","article-title":"RNA nucleotide methylation","volume":"2","author":"Motorin","year":"2011","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.taap.2014.01.017","article-title":"Oxidative stress\/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants","volume":"275","author":"Leone","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0074-7696(06)60002-8","article-title":"Molecular mechanism of phase I and phase II drug-metabolizing enzymes: Implications for detoxification","volume":"260","author":"Iyanagi","year":"2007","journal-title":"Int. Rev. Cytol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"94","DOI":"10.14412\/2074-2711-2016-2-94-99","article-title":"Chronic valproic acid intoxication in epileptology: Diagnosis and treatment","volume":"8","author":"Shnaider","year":"2016","journal-title":"Neurol. Neuropsychiatry Psychosom."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"343","DOI":"10.2174\/1381612825666190329145428","article-title":"Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update","volume":"25","author":"Guo","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1007\/BF00964959","article-title":"Studies on distribution and metabolism of valproate in rat brain, liver, and kidney","volume":"5","author":"Aly","year":"1980","journal-title":"Neurochem. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.2147\/DDDT.S357530","article-title":"Comprehensive Analysis of Metabolic Changes in Male Mice Exposed to Sodium Valproate Based on GC-MS Analysis","volume":"16","author":"Gao","year":"2022","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.tips.2011.08.005","article-title":"Cytochrome P450 enzymes in the brain: Emerging evidence of biological significance","volume":"32","author":"Ferguson","year":"2011","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s00467-013-2512-x","article-title":"The effects of sodium valproate on the renal function of children with epilepsy","volume":"29","author":"Knights","year":"2014","journal-title":"Pediatr. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1211\/0022357001774958","article-title":"Influence of nanoparticles on the brain-to-serum distribution and the metabolism of valproic acid in mice","volume":"52","author":"Darius","year":"2000","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1345\/aph.1M296","article-title":"The effect of carbapenem antibiotics on plasma concentrations of valproic acid","volume":"43","author":"Mancl","year":"2009","journal-title":"Ann. Pharmacother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/BF00684382","article-title":"Enzyme cytochemistry combined with electron microscopy, pharmacokinetics, and clinical chemistry for the evaluation of the effects of steady-state valproic acid concentrations on the mouse","volume":"83","author":"Graf","year":"1985","journal-title":"Histochemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0022-3476(94)70218-7","article-title":"Carnitine-dependent changes of metabolic fuel consumption during long-term treatment with valproic acid","volume":"125","author":"Melegh","year":"1994","journal-title":"J. Pediatr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"152585","DOI":"10.1016\/j.tox.2020.152585","article-title":"Involvement of CYP2E1-ROS-CD36\/DGAT2 axis in the pathogenesis of VPA-induced hepatic steatosis in vivo and in vitro","volume":"445","author":"Ma","year":"2020","journal-title":"Toxicology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1684\/epd.2021.1261","article-title":"A review of pharmacokinetic drug interactions between antimicrobial and antiseizure medications in children","volume":"23","author":"Zaccara","year":"2021","journal-title":"Epileptic Disord."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/8904_2012_170","article-title":"Therapeutic efficacy of magnesium valproate in succinic semialdehyde dehydrogenase deficiency","volume":"8","author":"Vanadia","year":"2013","journal-title":"JIMD Rep."},{"key":"ref_50","first-page":"e8782","article-title":"Parkinsonism: A Rare Adverse Effect of Valproic Acid","volume":"12","author":"Muralidharan","year":"2020","journal-title":"Cureus"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13148-021-01050-4","article-title":"Epigenetic evidence of an Ac\/Dc axis by VPA and SAHA","volume":"13","author":"Lunke","year":"2021","journal-title":"Clin. Epigenetics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/bdd.2328","article-title":"Changes in uridine 5\u2019-diphospho-glucuronosyltransferase 1A6 expression by histone deacetylase inhibitor valproic acid","volume":"43","author":"Sakakibara","year":"2022","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7580","DOI":"10.1523\/JNEUROSCI.22-17-07580.2002","article-title":"Brain-derived neurotrophic factor promotes the maturation of GABAergic mechanisms in cultured hippocampal neurons","volume":"22","author":"Yamada","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_54","first-page":"402","article-title":"Effect of valproate derivatives on human brain myo-inositol-1-phosphate (MIP) synthase activity and amphetamine-induced rearing","volume":"59","author":"Shaltiel","year":"2007","journal-title":"Pharmacol. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0006-8993(02)02362-4","article-title":"A role for protein kinase C and its substrates in the action of valproic acid in the brain: Implications for neural plasticity","volume":"934","author":"Watterson","year":"2002","journal-title":"Brain Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s11940-019-0558-1","article-title":"Current Status of Antiepileptic Drugs as Preventive Migraine Therapy","volume":"21","author":"Parikh","year":"2019","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13229-021-00428-8","article-title":"Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: Evidence of neuronal priming during early development in autism spectrum disorders","volume":"12","author":"Traetta","year":"2021","journal-title":"Mol. Autism."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1007\/s00018-007-7079-x","article-title":"The mechanisms of action of valproate in neuropsychiatric disorders: Can we see the forest for the trees?","volume":"64","author":"Rosenberg","year":"2007","journal-title":"Cell Mol. Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1111\/head.12550","article-title":"Acute Migraine Treatment in Adults","volume":"55","author":"Becker","year":"2015","journal-title":"Headache"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.schres.2006.07.015","article-title":"Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: Preliminary results from a clinical population","volume":"88","author":"Sharma","year":"2006","journal-title":"Schizophr. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1111\/bph.14058","article-title":"Epigenetic regulation of melatonin receptors in neuropsychiatric disorders","volume":"175","author":"Bahna","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s00228-020-02872-6","article-title":"Influence of CYP2C9 and CYP2A6 on plasma concentrations of valproic acid: A meta-analysis","volume":"76","author":"Yoon","year":"2020","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_63","first-page":"18","article-title":"Biological Markers Of The Antiepileptic Drugs Efficacy And Safety: Pharmacogenetics And Pharmacokinetics","volume":"1","author":"Nasyrova","year":"2017","journal-title":"Sib. Med. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/toxsci\/kfl096","article-title":"Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1\/*1 genotype","volume":"94","author":"Kiang","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.clineuro.2010.01.002","article-title":"The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients","volume":"112","author":"Tan","year":"2010","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1136\/ejhpharm-2020-002367","article-title":"Impact of CYP2C19 and CYP2C9 gene polymorphisms on sodium valproate plasma concentration in patients with epilepsy","volume":"29","author":"Song","year":"2022","journal-title":"Eur. J. Hosp. Pharm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"101678","DOI":"10.1016\/j.eclinm.2022.101678","article-title":"Comparative effectiveness of valproic acid in different serum concentrations for maintenance treatment of bipolar disorder: A retrospective cohort study using target trial emulation framework","volume":"54","author":"Chen","year":"2022","journal-title":"EClinicalMedicine"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/bcpt.12776","article-title":"Associations of CYP2C9 and CYP2A6 Polymorphisms with the Concentrations of Valproate and its Hepatotoxin Metabolites and Valproate-Induced Hepatotoxicity","volume":"121","author":"Zhao","year":"2017","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_69","unstructured":"Nasyrova, R.F., and Nesnanov, N.G. (2019). Pharmacogenetics. valproic acid. Clinical Psychopharmacogenetics: Monograph. Ad., Publisher House DEAN."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.eplepsyres.2017.02.015","article-title":"Association of CYP2C9, CYP2A6, ACSM2A, and CPT1A gene polymorphisms with adverse effects of valproic acid in Chinese patients with epilepsy","volume":"132","author":"Wang","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"536","DOI":"10.2133\/dmpk.DMPK-11-NT-144","article-title":"Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy","volume":"27","author":"Guo","year":"2012","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.2217\/pgs.11.64","article-title":"Association of genetic variants in six candidate genes with valproic acid therapy optimization","volume":"12","author":"Hung","year":"2011","journal-title":"Pharmacogenomics"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4362","DOI":"10.1038\/srep04362","article-title":"Soybean greatly reduces valproic acid plasma concentrations: A food-drug interaction study","volume":"4","author":"Marahatta","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00228-012-1277-7","article-title":"Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients","volume":"68","author":"Chu","year":"2012","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/S1734-1140(12)70900-3","article-title":"The multidrug transporter P-glycoprotein in pharmacoresistance to antiepileptic drugs","volume":"64","author":"Tomaszewski","year":"2012","journal-title":"Pharmacol. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1097\/FPC.0b013e3282f85e36","article-title":"Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs","volume":"18","author":"Hung","year":"2008","journal-title":"Pharmacogenet. Genomics."},{"key":"ref_77","first-page":"86","article-title":"Blood-brain barrier active efflux transporters: ATP-binding cassette gene family","volume":"2","author":"Potschka","year":"2005","journal-title":"J. Am. Soc. Exp. Neurother."},{"key":"ref_78","first-page":"29","article-title":"The influence of CYP2C9, CYP2C19 and ABCB1 polymorphisms on the plasma concentrations of valproic acid in epileptic patients","volume":"8","author":"Sabin","year":"2016","journal-title":"HVM Bioflux."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1056\/NEJMoa021986","article-title":"Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1","volume":"348","author":"Siddiqui","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1080\/00207454.2017.1412964","article-title":"Association between ABCB1 polymorphisms and response to first-generation antiepileptic drugs in a Tunisian epileptic population","volume":"128","author":"Ajmi","year":"2018","journal-title":"Int. J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.eplepsyres.2015.05.015","article-title":"ABCB1 G2677T\/A polymorphism is associated with the risk of drug-resistant epilepsy in Asians","volume":"115","author":"Yu","year":"2015","journal-title":"Epilepsy Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1111\/j.1442-200X.2010.03157.x","article-title":"Effect of CPS14217C>A genotype on valproic-acid-induced hyperammonemia","volume":"52","author":"Yagi","year":"2010","journal-title":"Pediatr. Int."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.eplepsyres.2019.05.010","article-title":"CPS1 T1405N polymorphism, HDL cholesterol, homocysteine and renal function are risk factors of VPA induced hyperammonemia among epilepsy patients","volume":"154","author":"Chen","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"R244","DOI":"10.1093\/hmg\/ddl233","article-title":"Mitochondrial DNA polymerase-gamma and human disease","volume":"15","author":"Hudson","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"57","DOI":"10.17650\/2073-8803-2018-13-1-57-63","article-title":"Problems of differential diagnosis of myoclon us-epilepsy associated with the mutation of the POLG gene and juvenile myoclonic epilepsy: A clinical case","volume":"13","author":"Shilkina","year":"2018","journal-title":"Russ. J. Child Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1002\/hep.23891","article-title":"Polymerase \u03b3 gene POLG determines the risk of sodium valproate-induced liver toxicity","volume":"52","author":"Stewart","year":"2010","journal-title":"Hepatology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"350","DOI":"10.24920\/003697","article-title":"POLG Mutations Are Probably Rare in the Han Chinese Population","volume":"35","author":"Yang","year":"2020","journal-title":"Chin. Med. Sci. J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.eplepsyres.2011.10.033","article-title":"Superoxide dismutase 2 Val16Ala polymorphism is a risk factor for the valproic acid-related elevation of serum aminotransferases","volume":"99","author":"Saruwatari","year":"2012","journal-title":"Epilepsy Res."},{"key":"ref_89","first-page":"993","article-title":"Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model","volume":"54","author":"Hsieh","year":"2013","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.psychres.2008.05.010","article-title":"Preliminary evidence on the association between XBP1-116C\/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders","volume":"168","author":"Kim","year":"2009","journal-title":"Psychiatry Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"pyv021","DOI":"10.1093\/ijnp\/pyv021","article-title":"Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid","volume":"18","author":"Li","year":"2015","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"82","DOI":"10.17116\/jnevro201811810282","article-title":"Pharmacogenetic markers of metabolic disorders in the treatment with valproic acid","volume":"118","author":"Drokov","year":"2018","journal-title":"Zhurnal Nevrol. Psikhiatrii Im. S.S. Korsakova"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Song, A., Cho, G.-W., Vijayakumar, K.A., Moon, C., Ang, M.J., Kim, J., Park, I., and Jang, C.H. (2021). Neuroprotective Effect of Valproic Acid on Salicylate-Induced Tinnitus. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010023"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/j.1528-1157.1993.tb02419.x","article-title":"Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity","volume":"34","author":"Siemes","year":"1993","journal-title":"Epilepsia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1097\/FPC.0b013e32835ea0b2","article-title":"Valproic acid pathway: Pharmacokinetics and pharmacodynamics","volume":"23","author":"Thorn","year":"2013","journal-title":"Pharm. Genom."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Beger, R.D., Schmidt, M.A., and Kaddurah-Daouk, R. (2020). Current Concepts in Pharmacometabolomics, Biomarker Discovery, and Precision Medicine. Metabolites, 10.","DOI":"10.3390\/metabo10040129"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"D622","DOI":"10.1093\/nar\/gkab1062","article-title":"HMDB 5.0: The Human Metabolome Database for 2022","volume":"50","author":"Wishart","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1124\/dmd.110.032938","article-title":"Identification of valproic acid glucuronide hydrolase as a key enzyme for the interaction of valproic acid with carbapenem antibiotics","volume":"38","author":"Suzuki","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0009-2797(01)00234-4","article-title":"Differential effect of valproate and its Delta2- and Delta4-unsaturated metabolites, on the beta-oxidation rate of long-chain and medium-chain fatty acids","volume":"137","author":"Silva","year":"2001","journal-title":"Chem. Biol. Interact."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0306-9877(90)90049-K","article-title":"Valproyl CoA: An active metabolite of valproate?","volume":"31","author":"Friel","year":"1990","journal-title":"Med. Hypotheses"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.bcp.2005.02.012","article-title":"Histone deacetylases inhibition and tumor cells cytotoxicity by CNS-active VPA constitutional isomers and derivatives","volume":"69","author":"Eyal","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1159\/000457485","article-title":"The valproic acid metabolite E-2-n-propyl-2-pentenoic acid does not induce spina bifida in the mouse","volume":"19","author":"Ehlers","year":"1992","journal-title":"Dev. Pharmacol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"504","DOI":"10.5607\/en.2019.28.4.504","article-title":"HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice","volume":"28","author":"Kim","year":"2019","journal-title":"Exp. Neurobiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.pbb.2009.08.001","article-title":"Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington\u2019s disease","volume":"94","author":"Geisz","year":"2009","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.2174\/1381612826666200113162641","article-title":"Excitotoxicity as a Target Against Neurodegenerative Processes","volume":"26","author":"Binvignat","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.7150\/ijbs.9898","article-title":"Preclinical and clinical investigations of mood stabilizers for Huntington\u2019s disease: What have we learned?","volume":"10","author":"Scheuing","year":"2014","journal-title":"Int. J. Biol. Sci."},{"key":"ref_107","first-page":"9678098","article-title":"Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells","volume":"2019","year":"2019","journal-title":"J. Immunol. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e8993","DOI":"10.1590\/1414-431x20208993","article-title":"VPA\/PLGA microfibers produced by coaxial electrospinning for the treatment of central nervous system injury","volume":"53","author":"Reis","year":"2020","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12974-018-1193-6","article-title":"Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-\u03baB pathway dependent of HDAC3","volume":"15","author":"Chen","year":"2018","journal-title":"J. Neuroinflammation."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ejphar.2018.07.057","article-title":"Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer","volume":"835","author":"Heers","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e007071","DOI":"10.1161\/CIRCEP.118.007071","article-title":"HDAC (Histone Deacetylase) Inhibitor Valproic Acid Attenuates Atrial Remodeling and Delays the Onset of Atrial Fibrillation in Mice","volume":"12","author":"Scholz","year":"2019","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/clpt.1986.144","article-title":"The effect of aspirin on valproic acid metabolism","volume":"40","author":"Abbott","year":"1986","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2133\/dmpk.23.293","article-title":"Role of Na+\/L-carnitine transporter (OCTN2) in renal handling of pivaloylcarnitine and valproylcarnitine formed during pivalic acid-containing prodrugs and valproic acid treatment","volume":"23","author":"Ohnishi","year":"2008","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1081\/CLT-120014645","article-title":"Valproic acid toxicity: Overview and management","volume":"40","author":"Sztajnkrycer","year":"2002","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s10545-013-9657-4","article-title":"Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases","volume":"37","author":"Ruiter","year":"2014","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_116","unstructured":"PubChem (2022, December 21). Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 125849, Valproylcarnitine, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Valproylcarnitine."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1080\/15563650902752376","article-title":"Carnitine in the treatment of valproic acid-induced toxicity","volume":"47","author":"Lheureux","year":"2009","journal-title":"Clin. Toxicol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0009-8981(85)90020-8","article-title":"Valproylcarnitine: A novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry","volume":"145","author":"Millington","year":"1985","journal-title":"Clin. Chim. Acta."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1053\/j.gastro.2019.04.023","article-title":"Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure","volume":"157","author":"Torres","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"89","DOI":"10.14412\/2074-2711-2017-1S-89-96","article-title":"Mechanisms of valproate-induced teratogenesis","volume":"9","author":"Dmitrenko","year":"2017","journal-title":"Neurol. Neuropsychiatry Psychosom."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1002\/phar.1965","article-title":"Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia","volume":"37","author":"Frenette","year":"2017","journal-title":"Pharmacotherapy"},{"key":"ref_122","unstructured":"Patel, A.R., and Nagalli, S. (2022, November 27). Valproate Toxicity, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK560898\/."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/0003-9861(83)90602-1","article-title":"Influence of valproic acid on hepatic carbohydrate and lipid metabolism","volume":"223","author":"Becker","year":"1983","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.bbrc.2013.05.088","article-title":"Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells","volume":"436","author":"Li","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_125","first-page":"96","article-title":"Drug-induced Parkinsonism","volume":"13","author":"Vaiman","year":"2021","journal-title":"Soc. Clin. Psychiatry"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.neuroscience.2014.02.028","article-title":"Neuroprotection by valproic acid in an intrastriatal rotenone model of Parkinson\u2019s disease","volume":"267","author":"Carriere","year":"2014","journal-title":"Neuroscience"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.amjopharm.2011.09.002","article-title":"Valproic acid-induced parkinsonism in the elderly: A comprehensive review of the literature","volume":"9","author":"Mahmoud","year":"2011","journal-title":"Am. J. Geriatr. Pharmacother."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11306-016-1066-x","article-title":"Pharmacometabolomics informs Pharmacogenomics","volume":"12","author":"Neavin","year":"2016","journal-title":"Metabolomics"},{"key":"ref_129","first-page":"e125","article-title":"Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability","volume":"3","author":"Lewis","year":"2014","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1056\/NEJMra1010600","article-title":"Genomics and drug response","volume":"364","author":"Wang","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_131","unstructured":"Nasyrova, R.F., and Neznanov, N.G. (2019). Clinical Psychopharmacogenetics, Publisher DEAN."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/clpt.2013.217","article-title":"Pharmacometabolomics Research Network. Pharmacometabolomics: Implications for clinical pharmacology and systems pharmacology","volume":"95","author":"Weinshilboum","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"108220","DOI":"10.1016\/j.yebeh.2021.108220","article-title":"Effects of l-carnitine supplementation in patients with childhood-onset epilepsy prescribed valproate","volume":"122","author":"Okumura","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/S2210-7401(12)70015-3","article-title":"Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: An overview of their mechanisms of action","volume":"36","author":"Poupon","year":"2012","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"107396","DOI":"10.1016\/j.pharmthera.2019.107396","article-title":"Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy","volume":"203","author":"Goossens","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/cpdd.790","article-title":"Pharmacokinetics and Pharmacodynamics of Ursodeoxycholic Acid in an Overweight Population with Abnormal Liver Function","volume":"10","author":"Yoon","year":"2021","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_137","first-page":"351","article-title":"Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: A Pilot Study","volume":"53","author":"Asgarshirazi","year":"2015","journal-title":"Acta Med. Iran."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.toxrep.2020.12.019","article-title":"Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues","volume":"8","author":"Plummer","year":"2020","journal-title":"Toxicol. Rep."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1007\/s13346-022-01147-0","article-title":"Three-dimensional (3D) liver cell models\u2014A tool for bridging the gap between animal studies and clinical trials when screening liver accumulation and toxicity of nanobiomaterials","volume":"12","author":"Tutty","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0740-5472(90)90036-P","article-title":"Detoxification with phenobarbital of alprazolam-dependent polysubstance abusers","volume":"7","author":"Ravi","year":"1990","journal-title":"J. Subst. Abuse Treat."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"26","DOI":"10.21103\/Article8(1)_OA3","article-title":"Process of Personalized Prescription of Valproic Acid as the Main Element of the Management of Epilepsy","volume":"8","author":"Bochanova","year":"2018","journal-title":"Int. J. Biomed."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/clpt.2010.250","article-title":"Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram\/escitalopram response biomarkers in depression: Pharmacometabolomics-informed pharmacogenomics","volume":"89","author":"Ji","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"61","DOI":"10.26442\/2075-1753_2017.19.1.61-68","article-title":"Personalized medicine: The view of a clinical pharmacologist","volume":"19","author":"Sychev","year":"2017","journal-title":"Cons. Med."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/1\/134\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:07:40Z","timestamp":1760119660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/1\/134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,16]]},"references-count":143,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["metabo13010134"],"URL":"https:\/\/doi.org\/10.3390\/metabo13010134","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,16]]}}}