{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:09:20Z","timestamp":1790179760730,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000374","name":"British Medical Association","doi-asserted-by":"publisher","award":["BMA Foundation Lift into Research Grant (2019)"],"award-info":[{"award-number":["BMA Foundation Lift into Research Grant (2019)"]}],"id":[{"id":"10.13039\/501100000374","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Artificial Organs"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Normothermic machine perfusion (NMP) provides a platform for drug\u2010delivery. However, pharmacological considerations for therapeutics delivered during NMP are scarcely reported. We aimed to demonstrate the ability of NMP as a platform for pharmacological testing, using a drug which increases metabolism (2,4\u2010dinitrophenol; DNP) as an example therapeutic.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed 25\u2009h of NMP on human livers which had been declined for transplant due to steatosis (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a07). Three livers received a DNP bolus, three were controls, and one received a DNP infusion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Toxicity studies revealed DNP delivery was safe, without hepatotoxic effects. The liver surface temperature was increased in the DNP group (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.046), but no livers suffered hyperthermia\u2014the mechanism of DNP toxicity in vivo. Pharmacokinetic studies revealed DNP elimination with first\u2010order kinetics and 7.7\u00a0h half\u2010life (95% CI\u00a0=\u00a05.1\u201315.9\u00a0hrs). The clearance of DNP in bile was negligible. As expected, DNP significantly increased oxygen consumption (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.023); this increase was closely correlated with perfusate DNP concentration (r\n                      <jats:sup>2<\/jats:sup>\n                      \u00a0=\u00a00.975;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.002) and the effect was lost as DNP was eliminated by the liver. A DNP infusion rate, calculated using our pharmacokinetic data, successfully maintained perfusate DNP concentration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Detailed pharmacological testing can be performed during NMP. Our therapeutic (DNP) is rapidly eliminated by the ex vivo liver, meaning the drug effect of increased metabolism is only transient. This demonstrates the importance of assessing pharmacokinetics when delivering therapeutics during NMP, especially for prolonged perfusion of organs with established roles in drug elimination. Rigorous pharmacological testing is needed to unlock the potential of NMP as a clinical drug\u2010delivery platform.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aor.14309","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T09:54:49Z","timestamp":1652349289000},"page":"2201-2214","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pharmacological testing of therapeutics using normothermic machine perfusion: A pilot study of 2,4\u2010dinitrophenol delivery to steatotic human livers"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5529-7815","authenticated-orcid":false,"given":"Samuel J.","family":"Tingle","sequence":"first","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"},{"name":"Department of HPB and Transplant Surgery Freeman Hospital  Newcastle upon Tyne UK"},{"name":"Blood and Transplant Research Unit Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily R.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"},{"name":"Department of HPB and Transplant Surgery Freeman Hospital  Newcastle upon Tyne UK"},{"name":"Blood and Transplant Research Unit Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Bates","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"},{"name":"Blood and Transplant Research Unit Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim K.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of HPB and Transplant Surgery Freeman Hospital  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Govaere","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Shuttleworth","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"},{"name":"Blood and Transplant Research Unit Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"},{"name":"Department of HPB and Transplant Surgery Freeman Hospital  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Palmer","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Bury","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"},{"name":"Department of Cellular Pathology Victoria Infirmary  Newcastle upon Tyne 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