{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:53:13Z","timestamp":1791276793281,"version":"4.1.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"the Technology Research Program Project of Qiandongnan Prefecture","award":["Grant No. (2025)0014"],"award-info":[{"award-number":["Grant No. (2025)0014"]}]},{"name":"Guizhou Provincial Science and Technology Program","award":["Grant No. QN(2026)003-38"],"award-info":[{"award-number":["Grant No. QN(2026)003-38"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Clin Pharmacol"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1007\/s00228-026-04189-2","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T01:54:48Z","timestamp":1790387688000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated metabolomic and pharmacogenomic analysis for prediction of valproic acid efficacy and hepatotoxicity in pediatric epilepsy"],"prefix":"10.1007","volume":"82","author":[{"given":"Changsong","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longkuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"4189_CR1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.2165\/00023210-200216100-00003","volume":"16","author":"W Loscher","year":"2002","unstructured":"Loscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16:669\u2013694","journal-title":"CNS Drugs"},{"key":"4189_CR2","doi-asserted-by":"publisher","first-page":"926","DOI":"10.2174\/1570159X17666181227165722","volume":"17","author":"M Romoli","year":"2019","unstructured":"Romoli M, Mazzocchetti P, D\u2019Alonzo R, Siliquini S, Rinaldi VE, Verrotti A, Calabresi P, Costa C (2019) Valproic Acid and Epilepsy: From Molecular Mechanisms to Clinical Evidences. Curr Neuropharmacol 17:926\u2013946","journal-title":"Curr Neuropharmacol"},{"key":"4189_CR3","doi-asserted-by":"crossref","unstructured":"Aaberg KM, Gunnes N, Bakken IJ, Lund Soraas C, Berntsen A, Magnus P, Lossius MI, Stoltenberg C, Chin R, Suren P (2017) Incidence and prevalence of childhood epilepsy: a nationwide cohort study. Pediatr 139","DOI":"10.1542\/peds.2016-3908"},{"key":"4189_CR4","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/1477-7525-1-36","volume":"1","author":"GM Ronen","year":"2003","unstructured":"Ronen GM, Streiner DL, Rosenbaum P (2003) Health-related quality of life in childhood epilepsy: moving beyond \u2018seizure control with minimal adverse effects\u2019. Health Qual Life Outcomes 1:36","journal-title":"Health Qual Life Outcomes"},{"key":"4189_CR5","doi-asserted-by":"publisher","first-page":"1483723","DOI":"10.3389\/fphar.2024.1483723","volume":"15","author":"H Yazbeck","year":"2024","unstructured":"Yazbeck H, Youssef J, Nasreddine W, El Kurdi A, Zgheib N, Beydoun A (2024) The role of candidate pharmacogenetic variants in determining valproic acid efficacy, toxicity and concentrations in patients with epilepsy. Front Pharmacol 15:1483723","journal-title":"Front Pharmacol"},{"key":"4189_CR6","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/jhg.2017.91","volume":"62","author":"MM Zhu","year":"2017","unstructured":"Zhu MM, Li HL, Shi LH, Chen XP, Luo J, Zhang ZL (2017) The pharmacogenomics of valproic acid. J Hum Genet 62:1009\u20131014","journal-title":"J Hum Genet"},{"key":"4189_CR7","first-page":"1239","volume-title":"Antiepileptic drugs\u2013best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring","author":"PN Patsalos","year":"2008","unstructured":"Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E (2008) Antiepileptic drugs\u2013best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, vol 49. ILAE Commission on Therapeutic Strategies, Epilepsia, pp 1239\u20131276"},{"key":"4189_CR8","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1080\/17425255.2020.1724956","volume":"16","author":"C Johannessen Landmark","year":"2020","unstructured":"Johannessen Landmark C, Johannessen SI, Patsalos PN (2020) Therapeutic drug monitoring of antiepileptic drugs: current status and future prospects. Expert Opin Drug Metab Toxicol 16:227\u2013238","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"4189_CR9","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1124\/dmd.123.001539","volume":"52","author":"RT Li","year":"2024","unstructured":"Li RT, Chen ZY, Tang SY, Wen DS, Ren RN, Zhang XX, Liu SZ, Zhou S, Wang XD, Zhou LM, Huang M (2024) Association of Valproic Acid and Its Main Metabolites\u2019 Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring. Drug Metab Dispos 52:210\u2013217","journal-title":"Drug Metab Dispos"},{"key":"4189_CR10","doi-asserted-by":"publisher","first-page":"1228641","DOI":"10.3389\/fphar.2023.1228641","volume":"14","author":"L Zhang","year":"2023","unstructured":"Zhang L, Liu M, Qin W, Shi D, Mao J, Li Z (2023) Modeling the protein binding non-linearity in population pharmacokinetic model of valproic acid in children with epilepsy: a systematic evaluation study. Front Pharmacol 14:1228641","journal-title":"Front Pharmacol"},{"key":"4189_CR11","first-page":"262","volume":"19","author":"H Lu","year":"2014","unstructured":"Lu H, Rosenbaum S (2014) Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther 19:262\u2013276","journal-title":"J Pediatr Pharmacol Ther"},{"key":"4189_CR12","doi-asserted-by":"crossref","unstructured":"Shnayder NA, Grechkina VV, Khasanova AK, Bochanova EN, Dontceva EA, Petrova MM, Asadullin AR, Shipulin GA, Altynbekov KS, Al-Zamil M, Nasyrova RF (2023) Therapeutic and toxic effects of valproic acid metabolites. Metabolites 13","DOI":"10.3390\/metabo13010134"},{"key":"4189_CR13","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1097\/FPC.0b013e32835ea0b2","volume":"23","author":"Y Ghodke-Puranik","year":"2013","unstructured":"Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE (2013) Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 23:236\u2013241","journal-title":"Pharmacogenet Genomics"},{"key":"4189_CR14","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s10545-008-0841-x","volume":"31","author":"MF Silva","year":"2008","unstructured":"Silva MF, Aires CC, Luis PB, Ruiter JP, L IJ, Duran M, Wanders RJ (2008) I. Tavares de Almeida, Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis 31:205\u2013216","journal-title":"J Inherit Metab Dis"},{"key":"4189_CR15","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1038\/clpt.2011.47","volume":"89","author":"KE Price","year":"2011","unstructured":"Price KE, Pearce RE, Garg UC, Heese BA, Smith LD, Sullivan JE, Kennedy MJ, Bale JF Jr., Ward RM, Chang TK, Abbott FS, Leeder JS (2011) Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study. Clin Pharmacol Ther 89:867\u2013874","journal-title":"Clin Pharmacol Ther"},{"key":"4189_CR16","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.2147\/DDDT.S357530","volume":"16","author":"Y Gao","year":"2022","unstructured":"Gao Y, Jiang D, Wang C, An G, Zhu L, Cui C (2022) Comprehensive Analysis of Metabolic Changes in Male Mice Exposed to Sodium Valproate Based on GC-MS Analysis. Drug Des Devel Ther 16:1915\u20131930","journal-title":"Drug Des Devel Ther"},{"key":"4189_CR17","first-page":"354671","volume":"2015","author":"A Zhang","year":"2015","unstructured":"Zhang A, Sun H, Yan G, Wang P, Wang X (2015) Metabolomics for Biomarker Discovery: Moving to the Clinic. Biomed Res Int 2015:354671","journal-title":"Biomed Res Int"},{"key":"4189_CR18","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41392-023-01399-3","volume":"8","author":"S Qiu","year":"2023","unstructured":"Qiu S, Cai Y, Yao H, Lin C, Xie Y, Tang S, Zhang A (2023) Small molecule metabolites: discovery of biomarkers and therapeutic targets. Signal Transduct Target Ther 8:132","journal-title":"Signal Transduct Target Ther"},{"key":"4189_CR19","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1002\/mas.20108","volume":"26","author":"K Dettmer","year":"2007","unstructured":"Dettmer K, Aronov PA, Hammock BD (2007) Mass spectrometry-based metabolomics. Mass Spectrom Rev 26:51\u201378","journal-title":"Mass Spectrom Rev"},{"key":"4189_CR20","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.drudis.2021.11.015","volume":"27","author":"Y Fu","year":"2022","unstructured":"Fu Y, Saraswat AL, Monpara J, Patel K (2022) Stromal disruption facilitating invasion of a \u2018nano-arsenal\u2019 into the solid tumor. Drug Discov Today 27:1132\u20131141","journal-title":"Drug Discov Today"},{"key":"4189_CR21","doi-asserted-by":"publisher","first-page":"15035","DOI":"10.1038\/s41598-019-51337-z","volume":"9","author":"L Boguszewicz","year":"2019","unstructured":"Boguszewicz L, Jamroz E, Ciszek M, Emich-Widera E, Kijonka M, Banasik T, Skorupa A, Sokol M (2019) NMR-based metabolomics in pediatric drug resistant epilepsy - preliminary results. Sci Rep 9:15035","journal-title":"Sci Rep"},{"key":"4189_CR22","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neulet.2017.01.014","volume":"667","author":"S Balestrini","year":"2018","unstructured":"Balestrini S, Sisodiya SM (2018) Pharmacogenomics in epilepsy. Neurosci Lett 667:27\u201339","journal-title":"Neurosci Lett"},{"key":"4189_CR23","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1097\/FTD.0000000000000337","volume":"38","author":"W Feng","year":"2016","unstructured":"Feng W, Mei S, Zhu L, Yu Y, Yang W, Gao B, Wu X, Zhao Z, Fang F (2016) Effects of UGT1A6 and GABRA1 on Standardized Valproic Acid Plasma Concentrations and Treatment Effect in Children With Epilepsy in China. Ther Drug Monit 38:738\u2013743","journal-title":"Ther Drug Monit"},{"key":"4189_CR24","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.seizure.2018.04.006","volume":"58","author":"W Feng","year":"2018","unstructured":"Feng W, Mei S, Zhu L, Yu Y, Yang W, Gao B, Wu X, Zhao Z, Fang F (2018) Effects of UGT2B7, SCN1A and CYP3A4 on the therapeutic response of sodium valproate treatment in children with generalized seizures. Seizure 58:96\u2013100","journal-title":"Seizure"},{"key":"4189_CR25","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1080\/17410541.2024.2441655","volume":"22","author":"C Wu","year":"2025","unstructured":"Wu C, Zheng J, Pan Y, Tao R, Zhong Z, Qian C, Liang H, Wu H (2025) Genetic and non-genetic factors influencing the therapeutic response of valproic acid in pediatric epileptic patients. Per Med 22:11\u201319","journal-title":"Per Med"},{"key":"4189_CR26","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1111\/epi.12028","volume":"54","author":"TA Glauser","year":"2013","unstructured":"Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Adamson PC (2013) Childhood Absence Epilepsy Study, Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 54:141\u2013155","journal-title":"Epilepsia"},{"key":"4189_CR27","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","volume":"51","author":"P Kwan","year":"2010","unstructured":"Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshe SL, Perucca E, Wiebe S, French J (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51:1069\u20131077","journal-title":"Epilepsia"},{"key":"4189_CR28","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41582-022-00651-8","volume":"18","author":"JM Rho","year":"2022","unstructured":"Rho JM, Boison D (2022) The metabolic basis of epilepsy. Nat Rev Neurol 18:333\u2013347","journal-title":"Nat Rev Neurol"},{"key":"4189_CR29","doi-asserted-by":"crossref","unstructured":"Parra M, Stahl S, Hellmann H (2018) Vitamin B(6) and its role in cell metabolism and physiology. Cells 7","DOI":"10.3390\/cells7070084"},{"key":"4189_CR30","doi-asserted-by":"publisher","first-page":"592514","DOI":"10.3389\/fneur.2020.592514","volume":"11","author":"Y Fei","year":"2020","unstructured":"Fei Y, Shi R, Song Z, Wu J (2020) Metabolic Control of Epilepsy: A Promising Therapeutic Target for Epilepsy. Front Neurol 11:592514","journal-title":"Front Neurol"},{"key":"4189_CR31","doi-asserted-by":"crossref","unstructured":"Tagliatti V, Descamps C, Lefevre M, Colet JM (2023) Predicting valproate-induced liver injury using metabolomic analysis of ex ovo chick embryo allantoic fluid. Metabolites 13","DOI":"10.3390\/metabo13060721"},{"key":"4189_CR32","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1080\/15563650902752376","volume":"47","author":"PE Lheureux","year":"2009","unstructured":"Lheureux PE, Hantson P (2009) Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 47:101\u2013111","journal-title":"Clin Toxicol (Phila)"},{"key":"4189_CR33","doi-asserted-by":"publisher","first-page":"254","DOI":"10.5808\/GI.2013.11.4.254","volume":"11","author":"JH Yi","year":"2013","unstructured":"Yi JH, Cho YJ, Kim WJ, Lee MG, Lee JH (2013) Genetic Variations of ABCC2 Gene Associated with Adverse Drug Reactions to Valproic Acid in Korean Epileptic Patients. Genomics Inf 11:254\u2013262","journal-title":"Genomics Inf"},{"key":"4189_CR34","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/toxsci\/kfl096","volume":"94","author":"TK Kiang","year":"2006","unstructured":"Kiang TK, Ho PC, Anari MR, Tong V, Abbott FS, Chang TK (2006) Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1\/*1 genotype. Toxicol Sci 94:261\u2013271","journal-title":"Toxicol Sci"}],"container-title":["European Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-026-04189-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00228-026-04189-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-026-04189-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:27:45Z","timestamp":1791275265000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00228-026-04189-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,26]]},"references-count":34,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["4189"],"URL":"https:\/\/doi.org\/10.1007\/s00228-026-04189-2","relation":{},"ISSN":["0031-6970","1432-1041"],"issn-type":[{"value":"0031-6970","type":"print"},{"value":"1432-1041","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,26]]},"assertion":[{"value":"2 July 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study protocol adhered to the principles of the Declaration of Helsinki and received approval from the institutional Ethics Committee (approval number: 2025-LS-244).","order":1,"name":"Ethics","label":"Human ethics and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was obtained from all participants included in the study.","order":2,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This work was supported by the Technology Research Program Project of Qiandongnan Prefecture [Grant No. (2025)0014; Guizhou, China] and Guizhou Provincial Basic Research Program (Natural Science) [Grant No. QianKeHeJiChu-QN (2026)003-38; Guizhou, China].","order":4,"name":"Ethics","label":"Financial support","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":5,"name":"Ethics","label":"Clinical trial number","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"259"}}