{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:46:09Z","timestamp":1788781569045,"version":"build-2803163510"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:00:00Z","timestamp":1663113600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5K01OD026526"],"award-info":[{"award-number":["5K01OD026526"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Vet Comparative Oncology"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cyclophosphamide (CP) is an alkylating agent commonly included in multi\u2010drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4\u2010hydroxycyclophosphamide (4\u2010OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto\u2010induction of metabolism in humans, with faster CP clearance and relatively increased 4\u2010OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200\u2013250\u2009mg\/m<jats:sup>2<\/jats:sup>over 3 to 4\u2009days in a prospectively identified population of cancer\u2010bearing dogs. Plasma concentrations of CP and 4\u2010OHCP were measured by ultra\u2010high performance liquid chromatography tandem\u2010mass spectrometry in eight dogs following the first and last doses to assess for auto\u2010induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73\u2009\u00b1\u20090.46 vs. 1.22\u2009\u00b1\u20090.5\u00a0h<jats:sup>\u22121<\/jats:sup>;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.125). Additionally, no significant difference in dose\u2010normalized 4\u2010OHCP exposure was identified between first and last doses (5.9\u2009\u00b1\u20092.1 vs. 7.9\u2009\u00b1\u20096.4\u00a0h\u2009\u00d7\u2009ng\/ml;<jats:italic>p<\/jats:italic>\u00a0=\u00a0.936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio\u2010activation of CP in dogs administered a dose of 200\u2013250\u2009mg\/m<jats:sup>2<\/jats:sup>.<\/jats:p>","DOI":"10.1111\/vco.12856","type":"journal-article","created":{"date-parts":[[2022,9,4]],"date-time":"2022-09-04T02:48:25Z","timestamp":1662259705000},"page":"20-27","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fractionated oral dosing and its effect on cyclophosphamide pharmacokinetics in dogs with high\u2010grade multicentric lymphoma"],"prefix":"10.1111","volume":"21","author":[{"given":"Sridhar","family":"Veluvolu","sequence":"first","affiliation":[{"name":"William R Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine University of California\u2014Davis Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-6226","authenticated-orcid":false,"given":"Jennifer L.","family":"Willcox","sequence":"additional","affiliation":[{"name":"William R Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine University of California\u2014Davis Davis California USA"},{"name":"Department of Surgical and Radiological Sciences School of Veterinary Medicine, University of California\u2014Davis Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0324-445X","authenticated-orcid":false,"given":"Katherine A.","family":"Skorupski","sequence":"additional","affiliation":[{"name":"William R Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine University of California\u2014Davis Davis California USA"},{"name":"Department of Surgical and Radiological Sciences School of Veterinary Medicine, University of California\u2014Davis Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9348-2293","authenticated-orcid":false,"given":"Sami","family":"Al\u2010Nadaf","sequence":"additional","affiliation":[{"name":"William R Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine University of California\u2014Davis Davis California USA"},{"name":"Department of Surgical and Radiological Sciences School of Veterinary Medicine, University of California\u2014Davis Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8047-3494","authenticated-orcid":false,"given":"Robert","family":"Rebhun","sequence":"additional","affiliation":[{"name":"William R Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine University of California\u2014Davis Davis California USA"},{"name":"Department of Surgical and Radiological Sciences School of Veterinary Medicine, University of California\u2014Davis Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5543-0724","authenticated-orcid":false,"given":"Luke","family":"Wittenburg","sequence":"additional","affiliation":[{"name":"Department of Surgical and Radiological Sciences School of Veterinary Medicine, University of California\u2014Davis Davis California 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