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Body\u2010on\u2010a\u2010chip (BOC) microfluidic devices, a subset of microphysiological systems (MPS), are being created to better predict human responses to drugs. Each BOC is designed with separate organ chambers interconnected with microfluidic channels mimicking blood recirculation. Here, we describe the design of the first pumpless, unidirectional, multiorgan system and apply this design concept for testing anticancer drug treatments. HCT\u2010116 colon cancer spheroids, HepG2\/C3A hepatocytes, and HL\u201060 promyeloblasts were embedded in collagen hydrogels and cultured within compartments representing \u201ccolon tumor\u201d, \u201cliver,\u201d and \u201cbone marrow\u201d tissue, respectively. Operating on a pumpless platform, the microfluidic channel design provides unidirectional perfusion at physiologically realistic ratios to multiple channels simultaneously. The metabolism\u2010dependent toxic effect of Tegafur, an oral prodrug of 5\u2010fluorouracil, combined with uracil was examined in each cell type. Tegafur\u2010uracil treatment induced substantial cell death in HCT\u2010116 cells and this cytotoxic response was reduced for multicellular spheroids compared to single cells, likely due to diffusion\u2010limited drug penetration. Additionally, off\u2010target toxicity was detected by HL\u201060 cells, which demonstrate that such systems can provide useful information on dose\u2010limiting side effects. Collectively, this microscale cell culture analog is a valuable physiologically\u2010based pharmacokinetic drug screening platform that may be used to support cancer drug development.<\/jats:p>","DOI":"10.1002\/btpr.3105","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T06:03:50Z","timestamp":1607061830000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pumpless, unidirectional microphysiological system for testing\n                    <scp>metabolism\u2010dependent<\/scp>\n                    chemotherapeutic toxicity"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3267-8321","authenticated-orcid":false,"given":"Danielle J.","family":"LaValley","sequence":"first","affiliation":[{"name":"Nancy E. and Peter C. 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