?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F22634%2F&rft.title=Metabolism+In+Vitro+of+the+Microtubule+Perturbagens%3A+Ceratamines+A+and+B&rft.creator=Smith%2C+Sara+E&rft.description=Ceratamines+A+and+B+are+heterocyclic+alkaloids+isolated+from+a+Pseudoceratina+sp.+marine+sponge.+These+natural+products+behave+as+antimitotic+agents+by+targeting+microtubules%2C+specifically+through+a+stabilization+mechanism.+Their+identification+led+to+the+discovery+of+a+novel+class+of+structurally+simple+microtubule+stabilizers%2C+with+implications+in+the+treatment+of+cancer+and+perhaps+tauopathies%2C+including+Alzheimer%E2%80%99s+disease.+To+date%2C+no+pre-clinical+studies+of+the+ceratamines+have+been+reported.+Therefore%2C+I+determined+the+phase+I+metabolism+of+each+compound+in+vitro.+Ceratamine+A+is+rapidly+metabolized+into+nine+phase+I+metabolites+by+rat+liver+microsomes%2C+while+ceratamine+B+only+yielded+five+metabolites.+The+majority+of+these+metabolites+were+formed+as+a+result+of+N-+and+O-dealkylations.+While+the+metabolites+formed+from+both+compounds+were+similar+when+incubated+with+human+liver+microsomes%2C+the+major+metabolites+were+not+the+same+as+those+from+rat+liver+microsomes.+The+aminoimidazole+is+the+most+metabolically+labile+site+in+rat+liver+microsomes%2C+however+the+dibrominated+aromatic+moiety+is+the+preferred+site+for+metabolism+in+human+liver+microsomes.+A+metabolic+stability+assay+revealed+that+both+compounds+have+a+high+estimated+clearance+in+rat+liver+microsomes%2C+but+they+appear+to+be+more+stable+in+human+liver+microsomes.+Ceratamine+B+was+estimated+to+have+a+moderate+clearance%2C+while+ceratamine+A+was+found+to+have+a+low+clearance.+Finally%2C+isozyme+mapping+and+small+molecule+inhibition+studies+revealed+that+the+specific+P450+isoforms+responsible+for+the+formation+of+two+major+metabolites+of+ceratamine+B+in+human+liver+microsomes+is+CYP3A4%2F5.&rft.date=2014-09-25&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F22634%2F1%2FSmith_Sara_E_PittETD_2014_2.pdf&rft.identifier=++Smith%2C+Sara+E++(2014)+Metabolism+In+Vitro+of+the+Microtubule+Perturbagens%3A+Ceratamines+A+and+B.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++