Loxoprofen Overdose without Toxicity: Pharmacokinetics of Loxoprofen and Metabolites Analysed by Liquid Chromatography–Mass Spectrometry: A Case Report

Loxoprofen Overdose without Toxicity: Pharmacokinetics of Loxoprofen and Metabolites Analysed by Liquid Chromatography–Mass Spectrometry: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Loxoprofen Overdose without Toxicity: Pharmacokinetics of Loxoprofen and Metabolites Analysed by Liquid Chromatography–Mass Spectrometry: A Case Report Daiki Mori, Jotaro Tachino, Kazuo Harada, Miyu Ueki, Kensuke Minami, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8812672/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background: Loxoprofen is a widely used nonsteroidal anti-inflammatory drug in Japan and a prodrug that is converted to its active trans-hydroxylated metabolite. Reports of loxoprofen overdose are extremely limited, and asymptomatic cases despite massive ingestion have not been previously documented. Case presentation: A 43-year-old woman ingested 8,280 mg of loxoprofen. She arrived at the hospital two hours later in a clinically stable condition. Laboratory tests and electrocardiography were unremarkable, and abdominal computed tomography revealed no gastric contents. She remained asymptomatic, with normal laboratory findings throughout the hospitalisation period, and was discharged on day 3. Pharmacokinetic analysis using liquid chromatography–mass spectrometry revealed markedly elevated plasma concentrations of loxoprofen and its metabolites two hours after ingestion (loxoprofen 159 μg/mL, trans-OH 64 μg/mL, cis-OH 29 μg/mL), which declined rapidly thereafter. Conclusion: This case suggests that markedly elevated plasma concentrations of loxoprofen and its metabolites do not necessarily result in toxicity. Pharmacokinetic findings indicate that rapid metabolism and excretion may prevent organ damage. Loxoprofen trans-OH metabolite cis-OH metabolite LC/MS Overdose Figures Figure 1 Figure 2 Background Loxoprofen is a prodrug converted in the liver by carbonyl reductase enzymes into trans- and cis-hydroxylated metabolites [ 1 ]. The active metabolite, trans-OH, exerts anti-inflammatory effects by inhibiting cyclooxygenase and suppressing prostaglandin synthesis [ 1 , 2 ]. Although loxoprofen is known to cause adverse effects such as renal and hepatic dysfunction and gastrointestinal disturbances [ 1 ], reports of overdose are extremely limited. To the best of our knowledge, no reported cases describe patients who remained asymptomatic despite elevated plasma concentrations of loxoprofen. Herein, we report a case of massive loxoprofen ingestion in which high plasma concentrations of loxoprofen and its metabolites were confirmed through liquid chromatography–mass spectrometry (LC/MS), but no toxic symptoms or organ dysfunction were observed. Case presentation Clinical course A 43-year-old Japanese woman (72 kg, 151 cm) intentionally ingested 8,280 mg of loxoprofen (138 tablets of Loxonin® 60 mg). She was transported to our hospital approximately two hours later. Her medical history included bipolar disorder. Uponn arrival, her vital signs were as follows: respiratory rate, 20/min; oxygen saturation, 97% on room air; heart rate, 82/min; blood pressure, 143/108 mmHg; and Glasgow Coma Scale score, 15 (E4V5M6). She was alert with no symptoms. Laboratory test results and electrocardiography findings were unremarkable. Computed tomography revealed no gastric contents; therefore, gastric lavage was not performed. Activated charcoal was administered, intravenous fluids were initiated, and she was admitted. Laboratory tests showed no organ dysfunction 8 hours post-ingestion, and physical examination revealed no gastrointestinal symptoms or oliguria. Oral intake resumed 13 hours after ingestion, and laboratory tests remained unremarkable throughout hospitalisation (Table 1). The patient remained clinically stable and asymptomatic throughout the course. Intravenous fluids were discontinued on day 3, and she was discharged home. Pharmacokinetic analysis The plasma concentrations of loxoprofen and its metabolites, trans-OH and cis-OH, were determined in collaboration with the Department of Legal Medicine, Graduate School of Medicine, the University of Osaka. Blood samples were centrifuged at 1500 rpm for 5 minutes at 5 ℃ to obtain plasma. Sodium citrate was used as an anticoagulant. Plasma samples were stored at -20 ℃ until pretreatment. Pretreatment was performed using the dispersive solid-phase extraction QuEChERS method, followed by LC/MS analysis in the multiple reaction monitoring mode. The initial screening of 260 compounds detected the presence of loxoprofen, trazodone, and caffeine [ 3 ]. Quantitative analyses were subsequently performed for these compounds, as well as for the trans- and cis-hydroxylated metabolites of loxoprofen, under chromatographic conditions that allowed the separation of the two isomers. Stable isotope-labelled internal standards were used for each target compound: loxoprofen-d₃, trazodone-d₆, caffeine- 13 C₃, trans-OH-d₃, and cis-OH-d₃. The concentrations of loxoprofen, trans-OH, and cis-OH are shown in Fig. 1 and Table 2. Trazodone was below the therapeutic range and caffeine was far below the toxic level, indicating no significant co-ingestion. Discussion We report a case of massive loxoprofen ingestion without clinical toxicity, suggesting that markedly elevated plasma concentrations of loxoprofen and its metabolites may not cause toxicity. We hypothesised that the absence of toxic symptoms may have been related to the rapid clearance of loxoprofen and its metabolites. After oral administration of 60 mg, the reported maximum plasma concentrations of loxoprofen, trans-OH, and cis-OH have been reported to be 5.04 ± 0.27 µg/mL, 0.85 ± 0.02 µg/mL, and 0.31 ± 0.04 µg/mL, respectively, with corresponding times to reach maximum concentration of 0.45 ± 0.03 hours, 0.79 ± 0.02 hours, and 0.73 ± 0.06 hours [ 4 ]. In contrast, in previous cases of 6000 mg and 3600 mg, plasma concentrations reached 52/24 µg/mL(cis-OH not measured) 4 hours after ingestion and 126/152/58.1 µg/mL 3.5 hours after ingestion for loxoprofen, trans-OH, and cis-OH, respectively, with clinical toxicity [ 5 , 6 ]. In this case, plasma concentrations measured 2 hours after ingestion were 159, 64, and 29 µg/mL, respectively. These levels were comparable to or exceeded those reported in previous studies (Fig. 2 ); nevertheless, no apparent toxic symptoms were observed. The estimated plasma half-lives of loxoprofen (1.7–2.5 hours) and trans-OH (2.7–4.9 hours) —calculated based on the terminal elimination phase of the observed time points—were shorter than the previously reported range of 6–12 hours [ 5 , 6 ], implying rapid metabolism and elimination before the development of organ dysfunction. Loxoprofen is mainly metabolised in the liver to trans-OH and cis-OH [ 1 , 4 ], which are subsequently excreted in urine [ 4 , 5 ]. Nonsteroidal anti-inflammatory drugs can cause dose-dependent hepatotoxicity [ 7 ], and trans-OH has been reported to contribute to renal impairment via the inhibition of prostaglandin biosynthesis [ 8 ]. Previous reports have suggested that drug-induced hepatic or renal dysfunction may lead to impaired metabolism and delayed elimination, resulting in reduced drug clearance [ 5 , 6 ]. In this case, preserved organ reserve in the absence of underlying disease, together with potential genetic factors and the benefit of early supportive therapy, might have contributed to more efficient drug metabolism and excretion. It is noteworthy that, although the concentration of the active metabolite trans-OH—which inhibits prostaglandin biosynthesis and can induce renal ischemia—reached levels comparable to toxic cases, renal function remained preserved. We speculate that the early initiation of intravenous fluid therapy maintained renal blood flow and promoted urinary excretion, thereby mitigating the risk of hemodynamically mediated acute kidney injury despite the high trans-OH exposure. Furthermore, loxoprofen is also metabolised by CYP3A4/3A5 to an inactive hydroxylated metabolite that competes with trans-OH formation [ 1 ]. Therefore, interindividual variability in CYP activity may influence metabolic balance and susceptibility to toxicity. In toxic cases, elevated plasma concentrations of loxoprofen and trans-OH persisted, and clinical symptoms developed within 1–2 days after ingestion. In contrast, in the present asymptomatic case, plasma concentrations declined more rapidly, suggesting limited duration of high-level exposure. Therefore, in patients who remain asymptomatic for 3 days after ingestion, hospital discharge may be considered with careful clinical assessment. Conclusions In this case, despite massive ingestion of loxoprofen, no toxicity or organ dysfunction was observed. LC/MS analysis revealed a relatively rapid decline in plasma concentrations of loxoprofen and its metabolites compared with previous reports, suggesting that early clearance may have prevented the development of toxicity. Abbreviations Liquid chromatography–mass spectrometry LC/MS Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for the publication of this case report. Competing interests The authors declare no competing interests Funding English-language editing and the article processing charge were supported by Rinku General Medical Center. Author Contribution DM contributed to drafting the manuscript. KH, MU and HM contributed to pharmacokinetic analysis. JT, KM, RT, TH, SN and JO were involved in the clinical management of this case, contributed to critical revision of the manuscript and gave final approval for the manuscript. All authors have read and approved the final manuscript. Acknowledgement We would like to thank all the medical staff who cooperated in the management of this case. Data Availability The data supporting the findings of this study are available from the corresponding author upon reasonable request. References Shrestha R, Cho PJ, Paudel S, Shrestha A, Kang MJ, Jeong TC et al. Exploring the metabolism of loxoprofen in liver microsomes: The role of cytochrome P450 and UDP-glucuronosyltransferase in its biotransformation. Pharmaceutics. 2018;10:112. https://doi.org/10.3390/pharmaceutics10030112 , PMID: 30072626. Jang JH, Kang HS, Jeong SH. Population Pharmacokinetics of loxoprofen and its alcoholic metabolites in healthy Korean men. Daru. 2024;32:631–48. https://doi.org/10.1007/s40199-024-00533-y , PMID: 39145828. Kuze H, Yoshida H, Tamagawa H, Nishihori T, Tokugawa Y, Yamamoto F et al. Evaluation of blood impurity removal efficiency using the QuEChERS method. Forensic Toxicol. 2025. https://doi.org/10.1007/s11419-025-00740-5 , PMID: 41051724. Naganuma H, Mochizuki Y, Kawahara Y. Study of Pharmacokinetics following oral administration of loxoprofen sodium(CS-600) in humans. J Clin Ther Med. 1986;2:1219–37. (in Japanese). Adachi K, Sugitani Y, Unita R, Yoshida K, Beppu S, Terashima M et al. Pharmacokinetics of loxoprofen in a self-administered overdose in a Japanese patient admitted to hospital. J Pharm Health Care Sci. 2021;7:33. https://doi.org/10.1186/s40780-021-00216-9 , PMID: 34488903. Miyoshi H, Sera A, Kato T, Kajiyama S, Kinoshita H. Acute drug overdose with loxoprofen: A case report. JJAAM. 2011;22:772–6. (in Japanese). Schmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ et al. Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int. 2016;36:603–9. https://doi.org/10.1111/liv.13032 , PMID: 26601797. Lucas GNC, Leitão ACC, Alencar RL, Xavier RMF, Daher EF, Junior GBD. Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs. J Bras Nefrol. 2019;41:124–30. https://doi.org/10.1590/2175-8239-JBN-2018-0107 , PMID: 30281062. Tables Table 1 to 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table 1: Laboratory data during hospitalisation Table2.xlsx Table 2: Serum concentrations of loxoprofen, trans-OH metabolite, and cis-OH metabolite after loxoprofen overdose Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Mar, 2026 Reviews received at journal 04 Mar, 2026 Reviews received at journal 03 Mar, 2026 Reviews received at journal 25 Feb, 2026 Reviewers agreed at journal 19 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers invited by journal 18 Feb, 2026 Editor assigned by journal 12 Feb, 2026 Submission checks completed at journal 12 Feb, 2026 First submitted to journal 07 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8812672","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":593729634,"identity":"8d505581-2b45-4847-a78c-3fceaaabc56a","order_by":0,"name":"Daiki 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Osaka","correspondingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Hirose","suffix":""},{"id":593729654,"identity":"92ed7853-cd06-4066-8ecf-7d200149241e","order_by":7,"name":"Shota Nakao","email":"","orcid":"","institution":"Rinku General Medical Center, Senshu Trauma and Critical Care Center","correspondingAuthor":false,"prefix":"","firstName":"Shota","middleName":"","lastName":"Nakao","suffix":""},{"id":593729657,"identity":"0420c93c-31ff-445c-ae91-abeeaf0f04b0","order_by":8,"name":"Hiroshi Matsumoto","email":"","orcid":"","institution":"Department of Legal Medicine, Graduate School of Medicine, The University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Matsumoto","suffix":""},{"id":593729658,"identity":"086bd601-95ad-4dac-9cfb-b9ed473b0e22","order_by":9,"name":"Jun Oda","email":"","orcid":"","institution":"Department of Traumatology and Acute Critical Medicine, Graduate School of Medicine, The University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Oda","suffix":""}],"badges":[],"createdAt":"2026-02-07 06:08:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8812672/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8812672/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103178882,"identity":"60712540-b545-4c78-9682-f323954c37c8","added_by":"auto","created_at":"2026-02-22 17:07:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":76617,"visible":true,"origin":"","legend":"\u003cp\u003eSerum concentrations of loxoprofen, trans-OH metabolite, and cis-OH metabolite after loxoprofen overdose. The vertical axis shows the loxoprofen, trans-OH metabolite, and cis-OH metabolite serum concentrations (μg/mL). The horizontal axis shows time after loxoprofen overdose (hours). 〇: loxoprofen, △: trans-OH metabolite, □: cis-OH metabolite.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8812672/v1/8187814253e285bfc662d05b.png"},{"id":103178884,"identity":"eb65061d-cf5c-4ad4-85d3-f4ae0a507d80","added_by":"auto","created_at":"2026-02-22 17:07:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":149652,"visible":true,"origin":"","legend":"\u003cp\u003eSerum concentrations of loxoprofen, trans-OH metabolite, and cis-OH metabolite in the present case were compared with those reported in two previous cases. The present case is indicated by circles (〇), and previously reported cases are represented by triangles (△) and squares (□).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8812672/v1/26b3c853f9f639a2929b3fc1.png"},{"id":104397555,"identity":"eec79b8f-4ab1-4cc1-9458-583da10cd4eb","added_by":"auto","created_at":"2026-03-11 11:51:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":647882,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8812672/v1/8aa1f7bc-2e47-4d91-b030-5aef3b93eda8.pdf"},{"id":103178883,"identity":"324f66fc-6b35-4cdb-b1cb-7a165e8a831b","added_by":"auto","created_at":"2026-02-22 17:07:12","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11411,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1: Laboratory data during hospitalisation\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8812672/v1/a2a295207b457a0b9f690718.xlsx"},{"id":103178885,"identity":"eedbf33f-9336-4c8a-97c5-167e053480fc","added_by":"auto","created_at":"2026-02-22 17:07:12","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10467,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2: Serum concentrations of loxoprofen, trans-OH metabolite, and cis-OH metabolite after loxoprofen overdose\u003c/p\u003e","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8812672/v1/2e53c837c869084ea691daf2.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Loxoprofen Overdose without Toxicity: Pharmacokinetics of Loxoprofen and Metabolites Analysed by Liquid Chromatography–Mass Spectrometry: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eLoxoprofen is a prodrug converted in the liver by carbonyl reductase enzymes into trans- and cis-hydroxylated metabolites [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The active metabolite, trans-OH, exerts anti-inflammatory effects by inhibiting cyclooxygenase and suppressing prostaglandin synthesis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although loxoprofen is known to cause adverse effects such as renal and hepatic dysfunction and gastrointestinal disturbances [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], reports of overdose are extremely limited. To the best of our knowledge, no reported cases describe patients who remained asymptomatic despite elevated plasma concentrations of loxoprofen.\u003c/p\u003e \u003cp\u003eHerein, we report a case of massive loxoprofen ingestion in which high plasma concentrations of loxoprofen and its metabolites were confirmed through liquid chromatography\u0026ndash;mass spectrometry (LC/MS), but no toxic symptoms or organ dysfunction were observed.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical course\u003c/h2\u003e \u003cp\u003eA 43-year-old Japanese woman (72 kg, 151 cm) intentionally ingested 8,280 mg of loxoprofen (138 tablets of Loxonin\u0026reg; 60 mg). She was transported to our hospital approximately two hours later. Her medical history included bipolar disorder.\u003c/p\u003e \u003cp\u003eUponn arrival, her vital signs were as follows: respiratory rate, 20/min; oxygen saturation, 97% on room air; heart rate, 82/min; blood pressure, 143/108 mmHg; and Glasgow Coma Scale score, 15 (E4V5M6). She was alert with no symptoms. Laboratory test results and electrocardiography findings were unremarkable. Computed tomography revealed no gastric contents; therefore, gastric lavage was not performed. Activated charcoal was administered, intravenous fluids were initiated, and she was admitted. Laboratory tests showed no organ dysfunction 8 hours post-ingestion, and physical examination revealed no gastrointestinal symptoms or oliguria. Oral intake resumed 13 hours after ingestion, and laboratory tests remained unremarkable throughout hospitalisation (Table\u0026nbsp;1). The patient remained clinically stable and asymptomatic throughout the course. Intravenous fluids were discontinued on day 3, and she was discharged home.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePharmacokinetic analysis\u003c/h3\u003e\n\u003cp\u003e The plasma concentrations of loxoprofen and its metabolites, trans-OH and cis-OH, were determined in collaboration with the Department of Legal Medicine, Graduate School of Medicine, the University of Osaka.\u003c/p\u003e \u003cp\u003eBlood samples were centrifuged at 1500 rpm for 5 minutes at 5 ℃ to obtain plasma. Sodium citrate was used as an anticoagulant. Plasma samples were stored at -20 ℃ until pretreatment. Pretreatment was performed using the dispersive solid-phase extraction QuEChERS method, followed by LC/MS analysis in the multiple reaction monitoring mode. The initial screening of 260 compounds detected the presence of loxoprofen, trazodone, and caffeine [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Quantitative analyses were subsequently performed for these compounds, as well as for the trans- and cis-hydroxylated metabolites of loxoprofen, under chromatographic conditions that allowed the separation of the two isomers. Stable isotope-labelled internal standards were used for each target compound: loxoprofen-d₃, trazodone-d₆, caffeine-\u003csup\u003e13\u003c/sup\u003eC₃, trans-OH-d₃, and cis-OH-d₃. The concentrations of loxoprofen, trans-OH, and cis-OH are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;2. Trazodone was below the therapeutic range and caffeine was far below the toxic level, indicating no significant co-ingestion.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe report a case of massive loxoprofen ingestion without clinical toxicity, suggesting that markedly elevated plasma concentrations of loxoprofen and its metabolites may not cause toxicity.\u003c/p\u003e \u003cp\u003eWe hypothesised that the absence of toxic symptoms may have been related to the rapid clearance of loxoprofen and its metabolites. After oral administration of 60 mg, the reported maximum plasma concentrations of loxoprofen, trans-OH, and cis-OH have been reported to be 5.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 \u0026micro;g/mL, 0.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 \u0026micro;g/mL, and 0.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 \u0026micro;g/mL, respectively, with corresponding times to reach maximum concentration of 0.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03 hours, 0.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 hours, and 0.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 hours [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In contrast, in previous cases of 6000 mg and 3600 mg, plasma concentrations reached 52/24 \u0026micro;g/mL(cis-OH not measured) 4 hours after ingestion and 126/152/58.1 \u0026micro;g/mL 3.5 hours after ingestion for loxoprofen, trans-OH, and cis-OH, respectively, with clinical toxicity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In this case, plasma concentrations measured 2 hours after ingestion were 159, 64, and 29 \u0026micro;g/mL, respectively. These levels were comparable to or exceeded those reported in previous studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e); nevertheless, no apparent toxic symptoms were observed. The estimated plasma half-lives of loxoprofen (1.7\u0026ndash;2.5 hours) and trans-OH (2.7\u0026ndash;4.9 hours) \u0026mdash;calculated based on the terminal elimination phase of the observed time points\u0026mdash;were shorter than the previously reported range of 6\u0026ndash;12 hours [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], implying rapid metabolism and elimination before the development of organ dysfunction.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eLoxoprofen is mainly metabolised in the liver to trans-OH and cis-OH [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], which are subsequently excreted in urine [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Nonsteroidal anti-inflammatory drugs can cause dose-dependent hepatotoxicity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and trans-OH has been reported to contribute to renal impairment via the inhibition of prostaglandin biosynthesis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Previous reports have suggested that drug-induced hepatic or renal dysfunction may lead to impaired metabolism and delayed elimination, resulting in reduced drug clearance [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In this case, preserved organ reserve in the absence of underlying disease, together with potential genetic factors and the benefit of early supportive therapy, might have contributed to more efficient drug metabolism and excretion. It is noteworthy that, although the concentration of the active metabolite trans-OH\u0026mdash;which inhibits prostaglandin biosynthesis and can induce renal ischemia\u0026mdash;reached levels comparable to toxic cases, renal function remained preserved. We speculate that the early initiation of intravenous fluid therapy maintained renal blood flow and promoted urinary excretion, thereby mitigating the risk of hemodynamically mediated acute kidney injury despite the high trans-OH exposure. Furthermore, loxoprofen is also metabolised by CYP3A4/3A5 to an inactive hydroxylated metabolite that competes with trans-OH formation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Therefore, interindividual variability in CYP activity may influence metabolic balance and susceptibility to toxicity.\u003c/p\u003e \u003cp\u003eIn toxic cases, elevated plasma concentrations of loxoprofen and trans-OH persisted, and clinical symptoms developed within 1\u0026ndash;2 days after ingestion. In contrast, in the present asymptomatic case, plasma concentrations declined more rapidly, suggesting limited duration of high-level exposure. Therefore, in patients who remain asymptomatic for 3 days after ingestion, hospital discharge may be considered with careful clinical assessment.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this case, despite massive ingestion of loxoprofen, no toxicity or organ dysfunction was observed. LC/MS analysis revealed a relatively rapid decline in plasma concentrations of loxoprofen and its metabolites compared with previous reports, suggesting that early clearance may have prevented the development of toxicity.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLiquid chromatography\u0026ndash;mass spectrometry\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLC/MS\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the patient for the publication of this case report.\u003c/p\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests\u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eEnglish-language editing and the article processing charge were supported by Rinku General Medical Center.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDM contributed to drafting the manuscript. KH, MU and HM contributed to pharmacokinetic analysis. JT, KM, RT, TH, SN and JO were involved in the clinical management of this case, contributed to critical revision of the manuscript and gave final approval for the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe would like to thank all the medical staff who cooperated in the management of this case.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShrestha R, Cho PJ, Paudel S, Shrestha A, Kang MJ, Jeong TC et al. Exploring the metabolism of loxoprofen in liver microsomes: The role of cytochrome P450 and UDP-glucuronosyltransferase in its biotransformation. Pharmaceutics. 2018;10:112. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/pharmaceutics10030112\u003c/span\u003e\u003cspan address=\"10.3390/pharmaceutics10030112\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, PMID: 30072626.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJang JH, Kang HS, Jeong SH. Population Pharmacokinetics of loxoprofen and its alcoholic metabolites in healthy Korean men. Daru. 2024;32:631\u0026ndash;48. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s40199-024-00533-y\u003c/span\u003e\u003cspan address=\"10.1007/s40199-024-00533-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, PMID: 39145828.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuze H, Yoshida H, Tamagawa H, Nishihori T, Tokugawa Y, Yamamoto F et al. Evaluation of blood impurity removal efficiency using the QuEChERS method. Forensic Toxicol. 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11419-025-00740-5\u003c/span\u003e\u003cspan address=\"10.1007/s11419-025-00740-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, PMID: 41051724.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaganuma H, Mochizuki Y, Kawahara Y. Study of Pharmacokinetics following oral administration of loxoprofen sodium(CS-600) in humans. J Clin Ther Med. 1986;2:1219\u0026ndash;37. (in Japanese).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdachi K, Sugitani Y, Unita R, Yoshida K, Beppu S, Terashima M et al. Pharmacokinetics of loxoprofen in a self-administered overdose in a Japanese patient admitted to hospital. J Pharm Health Care Sci. 2021;7:33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s40780-021-00216-9\u003c/span\u003e\u003cspan address=\"10.1186/s40780-021-00216-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, PMID: 34488903.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyoshi H, Sera A, Kato T, Kajiyama S, Kinoshita H. Acute drug overdose with loxoprofen: A case report. JJAAM. 2011;22:772\u0026ndash;6. (in Japanese).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ et al. Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int. 2016;36:603\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/liv.13032\u003c/span\u003e\u003cspan address=\"10.1111/liv.13032\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, PMID: 26601797.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLucas GNC, Leit\u0026atilde;o ACC, Alencar RL, Xavier RMF, Daher EF, Junior GBD. Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs. J Bras Nefrol. 2019;41:124\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1590/2175-8239-JBN-2018-0107\u003c/span\u003e\u003cspan address=\"10.1590/2175-8239-JBN-2018-0107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, PMID: 30281062.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijem","sideBox":"Learn more about [International Journal of Emergency Medicine](https://intjem.biomedcentral.com/)","snPcode":"12245","submissionUrl":"https://submission.nature.com/new-submission/12245/3","title":"International Journal of Emergency Medicine","twitterHandle":"@IntJEmergMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Loxoprofen, trans-OH metabolite, cis-OH metabolite, LC/MS, Overdose","lastPublishedDoi":"10.21203/rs.3.rs-8812672/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8812672/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground:\u003c/p\u003e\n\u003cp\u003eLoxoprofen is a widely used nonsteroidal anti-inflammatory drug in Japan and a prodrug that is converted to its active trans-hydroxylated metabolite. Reports of loxoprofen overdose are extremely limited, and asymptomatic cases despite massive ingestion have not been previously documented.\u003c/p\u003e\n\u003cp\u003eCase presentation:\u003c/p\u003e\n\u003cp\u003eA 43-year-old woman ingested 8,280 mg of loxoprofen. She arrived at the hospital two hours later in a clinically stable condition. Laboratory tests and electrocardiography were unremarkable, and abdominal computed tomography revealed no gastric contents. She remained asymptomatic, with normal laboratory findings throughout the hospitalisation period, and was discharged on day 3.\u003c/p\u003e\n\u003cp\u003ePharmacokinetic analysis using liquid chromatography–mass spectrometry revealed markedly elevated plasma concentrations of loxoprofen and its metabolites two hours after ingestion (loxoprofen 159 μg/mL, trans-OH 64 μg/mL, cis-OH 29 μg/mL), which declined rapidly thereafter.\u003c/p\u003e\n\u003cp\u003eConclusion:\u003c/p\u003e\n\u003cp\u003eThis case suggests that markedly elevated plasma concentrations of loxoprofen and its metabolites do not necessarily result in toxicity. Pharmacokinetic findings indicate that rapid metabolism and excretion may prevent organ damage.\u003c/p\u003e","manuscriptTitle":"Loxoprofen Overdose without Toxicity: Pharmacokinetics of Loxoprofen and Metabolites Analysed by Liquid Chromatography–Mass Spectrometry: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 17:07:07","doi":"10.21203/rs.3.rs-8812672/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-04T06:20:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-04T06:03:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-04T03:43:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-25T06:40:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"299048200601985108304951228349198468022","date":"2026-02-19T07:14:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"278923221881453002028035938386695494101","date":"2026-02-19T03:36:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"140769083860009633652659122836878344600","date":"2026-02-18T14:27:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-18T13:48:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-12T09:22:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-12T09:16:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Emergency Medicine","date":"2026-02-07T06:00:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijem","sideBox":"Learn more about [International Journal of Emergency Medicine](https://intjem.biomedcentral.com/)","snPcode":"12245","submissionUrl":"https://submission.nature.com/new-submission/12245/3","title":"International Journal of Emergency Medicine","twitterHandle":"@IntJEmergMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0be3895c-afaf-42ee-894e-786d185d8bb3","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-05T08:23:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 17:07:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8812672","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8812672","identity":"rs-8812672","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}