{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:38:22Z","timestamp":1760297902734,"version":"3.28.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2008,2,1]],"date-time":"2008-02-01T00:00:00Z","timestamp":1201824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>This study tested the hypothesis that the determinants of mild liver injury are prerequisites for more severe idiosyncratic hepatotoxicity. This study verified whether the possible risk factors for rare idiosyncratic valproic acid (VPA)-induced hepatotoxicity, VPA clearance and\/or serum carnitine concentrations are common to those for a mild elevation in transaminases in VPA-treated patients. VPA clearance was calculated in 172 Japanese patients with epilepsy, using a non-linear mixed-effects regression program. Carnitine concentrations were determined in a subset of 60 patients. The relationships between VPA clearance, carnitine concentration and levels of transaminases and ammonia were evaluated by Pearson's correlation coefficients. The final model of VPA apparent clearance (CL\/F) was as follows: CL\/F (L h\u22121) = 0.012 \u00d7 (BW\/40)0.34 \u00d7 dose0.55 \u00d7 0.90gender \u00d7 1.32PHT \u00d7 1.11CBZ \u00d7 1.12PB, where BW = total body weight (kg); gender = 1 if female, 0 if male; PHT\/CBZ\/PB = 1 if phenytoin, carbamazepine, or phenobarbital, respectively, is coadministrated, otherwise 0. Either a higher VPA clearance or acyl\/free carnitine ratio and a lower total and\/or free carnitine concentration, but not VPA concentration, were associated with the mild elevation in transaminases or ammonia. These results support the initial hypothesis, while also helping to clarify the mechanism of severe idiosyncratic hepatotoxicity with VPA.<\/jats:p>","DOI":"10.1211\/jpp.60.2.0017","type":"journal-article","created":{"date-parts":[[2008,1,22]],"date-time":"2008-01-22T00:48:07Z","timestamp":1200962887000},"page":"267-272","source":"Crossref","is-referenced-by-count":11,"title":["Potential relationships between transaminase abnormality and valproic acid clearance or serum carnitine concentrations in Japanese epileptic patients"],"prefix":"10.1093","volume":"60","author":[{"given":"Shuji","family":"Goto","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Seo","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Ueda","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyuko","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Kumamoto University Medical School , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiro","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Kumamoto University Medical School , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukio","family":"Ando","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Kumamoto University Medical School , Kumamoto,","place":["Japan"]},{"name":"Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takateru","family":"Ishitsu","sequence":"additional","affiliation":[{"name":"Kumamoto Saishunso National Hospital , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuko","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2008,2,1]]},"reference":[{"key":"2024103109361026900_cit1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1006\/rtph.1998.1201","article-title":"Serum transaminase elevations as indicators of hepatic injury following the administration of drugs","volume":"27","author":"Amacher","year":"1998","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"2024103109361026900_cit2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/sj.bjc.6603851","article-title":"Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial","volume":"97","author":"Atmaca","year":"2007","journal-title":"Br. J. Cancer"},{"key":"2024103109361026900_cit3","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1212\/WNL.56.10.1405","article-title":"Effect of L-carnitine treatment for valptoate-induced hepatotoxicity","volume":"56","author":"Bohan","year":"2001","journal-title":"Neurology"},{"key":"2024103109361026900_cit4","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1212\/WNL.46.2.465","article-title":"Valproic acid hepatic fatalities. III. U. 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