{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:02:44Z","timestamp":1784541764345,"version":"3.55.0"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Seizures are a common reason for drugs to fail during development, but they are difficult to predict preclinically. Enoxacin, a fluoroquinolone, rarely causes convulsions as a monotherapy, but convulsions have been seen after combination therapy with fenbufen, a nonsteroidal antiinflammatory drug. The interaction between the drugs is thought to result from inhibition of GABAA receptors, which are not their primary targets. Here, we show that, among 15 marketed fluoroquinolones and 1 active metabolite, 6, including enoxacin, inhibited \u03b3-aminobutyric acid (GABA)-evoked depolarization in cells expressing human GABAA receptors when administered with felbinac, the active metabolite of fenbufen. Within these 6, except for a prodrug, possessed a piperazinyl group at the seventh position of the quinolone ring. We also administered enoxacin or norfloxacin plus felbinac to rats and determined the cerebrospinal fluid concentrations of each drug when convulsions occurred. As we previously reported, an increase in network burst frequency recorded from primary cultured rat cortical neurons on microelectrode arrays is a risk marker for seizures, so we tested whether this assay could predict seizures induced by drug interactions between fluoroquinolones and felbinac. When co-administered with felbinac, only those fluoroquinolones that inhibited GABA currents in patch-clamp tests increased network burst frequency. Principal component analysis using 17 microelectrode array parameters supported that the mechanism of action was due to GABA antagonism in rodent neurons. Thus, the microelectrode array assay predicted seizure risks from the combination of enoxacin and the active metabolite of fenbufen and identified other fluoroquinolones with seizure risk potential.<\/jats:p>","DOI":"10.1093\/toxsci\/kfag039","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:35:16Z","timestamp":1774355716000},"source":"Crossref","is-referenced-by-count":0,"title":["In vitro and preclinical assessment of drug interactions between fluoroquinolones and a nonsteroidal antiinflammatory drug predicting risk of seizure"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1410-6979","authenticated-orcid":false,"given":"Yuki","family":"Seki","sequence":"first","affiliation":[{"name":"Integrated ADMET Science, Biopharmaceutical Assessments Function, Eisai Co., Ltd ., Tsukuba, Ibaraki 300-2635,","place":["Japan"]},{"name":"Laboratory of Genomics-based Drug Discovery, Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, Degree Program in Comprehensive Human Sciences, University of Tsukuba , Tsukuba, Ibaraki 305-8577,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikue","family":"Mihara","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]},{"name":"Tsukuba Branch, Business Controlling Department, TechnoPro, Inc. TechnoPro R&D Company , Tsuchiura, Ibaraki 300-0037,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taroumaru","family":"Okawa","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]},{"name":"Tsukuba Branch, Business Controlling Department, TechnoPro, Inc. TechnoPro R&D Company , Tsuchiura, Ibaraki 300-0037,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Ojima","sequence":"additional","affiliation":[{"name":"Tsukuba Branch, Business Controlling Department, TechnoPro, Inc. TechnoPro R&D Company , Tsuchiura, Ibaraki 300-0037,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumasa","family":"Aoyama","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]},{"name":"Pharmacological Evaluation Unit, Tsukuba Division, Sunplanet Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Mikamoto","sequence":"additional","affiliation":[{"name":"Global Drug Metabolism and Pharmacokinetics, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Morimitsu","sequence":"additional","affiliation":[{"name":"Molecular Profiling Department, Discovery Concept Validation Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeo","family":"Kamakura","sequence":"additional","affiliation":[{"name":"Molecular Profiling Department, Discovery Concept Validation Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuaki","family":"Goto","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoi","family":"Odawara","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Oshiro","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohiro","family":"Shiotani","sequence":"additional","affiliation":[{"name":"Global Drug Safety, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Yoshinaga","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Asakura","sequence":"additional","affiliation":[{"name":"Global Drug Safety, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Ishibashi","sequence":"additional","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology, Taihaku-ku , Sendai, Miyagi 982-8577,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology, Taihaku-ku , Sendai, Miyagi 982-8577,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology, Taihaku-ku , Sendai, Miyagi 982-8577,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0391-1339","authenticated-orcid":false,"given":"Norimasa","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Advanced Biosignal Safety Assessment, Biopharmaceutical Assessments Function, Eisai Co., Ltd. , Tsukuba, Ibaraki 300-2635,","place":["Japan"]},{"name":"Department of Electronics, 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