{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:33:27Z","timestamp":1792794807269,"version":"4.5.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T00:00:00Z","timestamp":1591920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Southern Denmark and CelVivo","id":[{"id":"https:\/\/ror.org\/03yrrjy16","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Medicines are usually prescribed for repeated use over shorter or longer times. Unfortunately, repeated-dose animal toxicity studies do not correlate well with observations in man. As emphasized by the \u20183Rs\u2019 and the desire to phase-out animal research, in vitro models are needed. One potential approach uses clinostat-cultured 3D HepG2\u2013C3A liver-mimetic spheroids. They take 18\u00a0days to recover in vivo physiological functionality and reach a metabolic equilibrium, which is thereafter stable for a year. Acute and chronic repeated-dose studies of six drugs (amiodarone, diclofenac, metformin, phenformin, paracetamol and valproic acid) suggest that spheroids are more predictive of human in vivo toxicity than either 2D-cultured HepG2 cells or primary human hepatocytes. Repeated non-lethal treatment results in a clear response and return to equilibrium. Mitochondrial toxic compounds can be identified using a galactose-based medium. Some drugs induced a protective (or stress) response that intensifies after the second treatment. This 3D spheroid model is inexpensive, highly reproducible and well-suited for the determination of repeated-dose toxicity of compounds (naturally or chemically synthesized).<\/jats:p>","DOI":"10.1093\/toxres\/tfaa033","type":"journal-article","created":{"date-parts":[[2020,5,13]],"date-time":"2020-05-13T15:46:01Z","timestamp":1589384761000},"page":"379-389","source":"Crossref","is-referenced-by-count":9,"title":["Response to and recovery from treatment in human liver-mimetic clinostat spheroids: a model for assessing repeated-dose drug toxicity"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6463-9477","authenticated-orcid":false,"given":"Stephen J","family":"Fey","sequence":"first","affiliation":[{"name":"CelVivo ApS, Middelfartvej 469, DK-5491 Blommenslyst, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6856-6703","authenticated-orcid":false,"given":"Barbara","family":"Korzeniowska","sequence":"additional","affiliation":[{"name":"CelVivo ApS, Middelfartvej 469, DK-5491 Blommenslyst, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0381-4523","authenticated-orcid":false,"given":"Krzysztof","family":"Wrzesinski","sequence":"additional","affiliation":[{"name":"CelVivo ApS, Middelfartvej 469, DK-5491 Blommenslyst, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,12]]},"reference":[{"key":"2020090213223733600_ref1","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1080\/01926230590522121","article-title":"Do preclinical testing strategies help predict human hepatotoxic potentials?","volume":"33","author":"Peters","year":"2005","journal-title":"Toxicol 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