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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.coverage.spatialNetherlandsen_US
dc.date.accessioned2019-10-08T15:39:25Z
dc.date.issued2019-11-01en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30953752en_US
dc.identifierS0928-0987(19)30142-3en_US
dc.identifier.citationEur J Pharm Sci, 2019, 139 pp. 104899 - ?en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3375
dc.identifier.eissn1879-0720en_US
dc.identifier.doi10.1016/j.ejps.2019.04.004en_US
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 (CLint) 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 CLint in both hepatocytes and liver microsomes of human, dog, minipig and rat, but considerably higher CLint 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.en_US
dc.format.extent104899 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectIn vitro metabolismen_US
dc.subjectMetabolite identificationen_US
dc.subjectReaction phenotypingen_US
dc.subjectToxicology speciesen_US
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.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-04-02en_US
rioxxterms.versionofrecord10.1016/j.ejps.2019.04.004en_US
rioxxterms.licenseref.startdate2019-11-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfEur J Pharm Scien_US
pubs.notesNot knownen_US
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/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 (including Analytical Chemistry)
pubs.publication-statusPublisheden_US
pubs.volume139en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamDrug Target Discoveryen_US
icr.researchteamMedicinal Chemistry 1 (including Analytical Chemistry)en_US
dc.contributor.icrauthorLinardopoulos, Spyridonen_US
dc.contributor.icrauthorBavetsias, Vassiliosen_US
dc.contributor.icrauthorRaynaud, Florenceen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/