{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:22:06Z","timestamp":1790803326490,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T00:00:00Z","timestamp":1582156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Chinese National major research and development program \"precision medicine research\" special project","award":["2017YFC0908800"],"award-info":[{"award-number":["2017YFC0908800"]}]},{"name":"Chinese Major Scientific & Technological Special Project of China","award":["2017ZX09304017"],"award-info":[{"award-number":["2017ZX09304017"]}]},{"name":"Chinese National Science & Technology Major Special Project on Major New Drug Innovation","award":["2018ZX09711003-006"],"award-info":[{"award-number":["2018ZX09711003-006"]}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vancomycin is a first\u2010line treatment for invasive infections caused by multidrug\u2010resistant gram\u2010positive bacteria. However, vancomycin\u2010induced nephrotoxicity is an increasing burden, particularly in patients with complex life\u2010threatening conditions. Vancomycin\u2010induced nephrotoxicity associated with clinically relevant exposure on the target site has not been well defined. This study aimed to acquire the concentration of vancomycin in the renal tubules and kidneys in humans using physiologically based pharmacokinetic (PBPK) modeling and simulation. Based upon the exposure of vancomycin in the renal tubule, the toxicity of vancomycin in human renal proximal tubular epithelial cells was examined with the XTT assay and in vitro metabolomics analysis. A rat PBPK model predicting plasma and kidney concentration\u2010time profiles of vancomycin matched the observed behavior after a single administration of 10 mg\/kg. The concentration of vancomycin in renal tubules was about 40\u201050 times higher than that in plasma. The human PBPK model transferred from the rat model predicted renal tubule concentrations of vancomycin as 316.1\u20102136.6 \u03bcg\/mL at 500 mg every 6 hours, and 199.0\u20103932.5 \u03bcg\/mL at 1000 mg every 12 hours. Vancomycin showed significant nephrotoxicity at 4 mg\/mL in XTT assessment. In total, 11 lysophosphatidylcholines and one lysophosphatidylethanolamine were identified by metabolomics analysis. The concentration\u2010dependent increase was evident in the release of lysophospholipids after vancomycin treatment (0.125\u20104 mg\/mL) for 24 hours. Our study revealed the relationship between the exposure of vancomycin in the kidney and toxicity of vancomycin at clinically relevant concentrations achieved from a mechanical PBPK model. A series of lysophospholipids as potential metabolic markers of renal toxicity were identified.<\/jats:p>","DOI":"10.1002\/jat.3951","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T17:23:38Z","timestamp":1582219418000},"page":"897-907","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["New insights into the vancomycin\u2010induced nephrotoxicity using in vitro metabolomics combined with physiologically based pharmacokinetic modeling"],"prefix":"10.1002","volume":"40","author":[{"given":"Haiyan","family":"Du","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Beijing Anzhen Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and Toxicology  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Cardiac Intensive Care, Beijing Anzhen Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Anzhen Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxiang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Otolaryngological, Beijing Anzhen Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Anzhen Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0732-3692","authenticated-orcid":false,"given":"Xiaomei","family":"Zhuang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and Toxicology  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2014.02.007"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2012.02.038"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/2042018816638223"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02535-16"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep38868"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0917-z"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1984.260"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.2165\/11537430-000000000-00000"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2018.12.014"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200948030-00004"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.3109\/09687688.2013.828855"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.10.086"},{"key":"e_1_2_7_14_1","first-page":"379","article-title":"Vancomycin nephrotoxicity: myths and facts","volume":"69","author":"Gupta A.","year":"2011","journal-title":"The Netherlands Journal of Medicine"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000452427"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.31.3.393"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S109485"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/704382"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00301.2011"},{"key":"e_1_2_7_20_1","first-page":"1","article-title":"Parameters for pyrethroid insecticide QSAR and PBPK\/PD models for human risk assessment","volume":"219","author":"Knaak J. B.","year":"2012","journal-title":"Reviews of Environmental Contamination and Toxicology"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/js9801135"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000006023"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2010.07.038"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2010.04.031"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.09.026"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/1071576031000061002"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2005.07.009"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1590\/0074-0276140120"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-016-0475-3"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00591-16"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010510-100540"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2017.02.025"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2007.08.008"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.509"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012101041"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-012-1863-5"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkw254"},{"key":"e_1_2_7_38_1","doi-asserted-by":"crossref","first-page":"e01684","DOI":"10.1128\/AAC.01684-17","article-title":"Identification of vancomycin exposure\u2010toxicity thresholds in hospitalized patients receiving intravenous vancomycin","volume":"62","author":"Zasowski E. J.","year":"2018","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2016.04.004"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjat.3951","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.3951","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jat.3951","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.3951","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:20:02Z","timestamp":1760530802000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.3951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,20]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2020,7]]}},"alternative-id":["10.1002\/jat.3951"],"URL":"https:\/\/doi.org\/10.1002\/jat.3951","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"value":"0260-437X","type":"print"},{"value":"1099-1263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,20]]},"assertion":[{"value":"2019-11-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}