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dc.contributor.authorWood, FLen_US
dc.contributor.authorShepherd, Sen_US
dc.contributor.authorHayes, Aen_US
dc.contributor.authorLiu, Men_US
dc.contributor.authorGrira, Ken_US
dc.contributor.authorMok, Yen_US
dc.contributor.authorAtrash, Ben_US
dc.contributor.authorFaisal, Aen_US
dc.contributor.authorBavetsias, Ven_US
dc.contributor.authorLinardopoulos, Sen_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorRaynaud, FIen_US
dc.date.accessioned2019-10-08T15:39:25Z
dc.date.issued2019-11
dc.identifier.citationEuropean journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2019, 139 pp. 104899 - ?
dc.identifier.issn0928-0987
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3375
dc.identifier.eissn1879-0720
dc.identifier.doi10.1016/j.ejps.2019.04.004
dc.description.abstractCCT241736 is a dual fms-like tyrosine kinase 3 (FLT3)/Aurora kinase inhibitor in development for the treatment of acute myeloid leukaemia. The successful development of any new drug relies on adequate safety testing including preclinical toxicology studies. Selection of an appropriate preclinical species requires a thorough understanding of the compound's metabolic clearance and pathways, as well as other pharmacokinetic and pharmacodynamic considerations. In addition, elucidation of the metabolising enzymes in human facilitates improved clinical prediction based on population pharmacokinetics and can inform drug-drug interaction studies. Intrinsic clearance (CL int ) determination and metabolite profiling of CCT241736 in human and four preclinical species (dog, minipig, rat and mouse) was undertaken in cryopreserved hepatocytes and liver microsomes. Recombinant human cytochrome P450 bactosomes (rCYP) were utilised to provide reaction phenotyping data and support prediction of metabolic pathways. CCT241736 exhibited low CL int in both hepatocytes and liver microsomes of human, dog, minipig and rat, but considerably higher CL int in mouse. CYP3A4 and CYP3A5 were identified as the major enzymes responsible for biotransformation of CCT241736 in human, exclusively forming five out of seven metabolites. Minipig showed greatest similarity to human with regard to both overall metabolic profile and abundance of specific metabolites relative to parent compound, and is therefore proposed as the most appropriate toxicological species. The greatest disparity was observed between human and dog. Based on metabolic profile, either mouse or rat is a suitable rodent species for toxicology studies.
dc.formatPrint-Electronic
dc.format.extent104899 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectMicrosomes, Liver
dc.subjectHepatocytes
dc.subjectAnimals
dc.subjectMice, Inbred ICR
dc.subjectSwine
dc.subjectSwine, Miniature
dc.subjectDogs
dc.subjectHumans
dc.subjectRats, Sprague-Dawley
dc.subjectPiperazines
dc.subjectCytochrome P-450 Enzyme System
dc.subjectProtein Kinase Inhibitors
dc.subjectDrug Evaluation, Preclinical
dc.subjectToxicity Tests
dc.subjectSpecies Specificity
dc.subjectFemale
dc.subjectMale
dc.subjectfms-Like Tyrosine Kinase 3
dc.subjectAurora Kinases
dc.titleMetabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in preclinical and human in vitro models: Implication for the choice of toxicology species.
dc.typeJournal Article
dcterms.dateAccepted2019-04-02
rioxxterms.versionofrecord10.1016/j.ejps.2019.04.004
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfEuropean journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1
pubs.publication-statusPublished
pubs.volume139
pubs.embargo.termsNot known
icr.researchteamDrug Target Discoveryen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
dc.contributor.icrauthorLinardopoulos, Spyridonen
dc.contributor.icrauthorBavetsias, Vassiliosen
dc.contributor.icrauthorRaynaud, Florenceen


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