Profiling of hepatic clearance pathways of Pittsburgh compound B and human liver cytochrome p450 phenotyping 英文参考文献.docVIP

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Profiling of hepatic clearance pathways of Pittsburgh compound B and human liver cytochrome p450 phenotyping 英文参考文献.doc

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Profiling of hepatic clearance pathways of Pittsburgh compound B and human liver cytochrome p450 phenotyping 英文参考文献

VanVlaslaeretal.EJNMMIResearch2013,3:10 /content/3/1/10 SHORT COMMUNICATION OpenAccess Profilingofhepaticclearancepathwaysof PittsburghcompoundBandhumanliver cytochromep450phenotyping AnneVanVlaslaer1,RussellJMortishire-Smith1,ClaireMackie1,XavierLanglois2,3andMarkESchmidt4* Abstract Background: 11C-PiBhasbeendevelopedasapositron-emissiontomography(PET)ligandforevaluatingfibrillarβ- amyloid(Aβ)inthehumanbrain.Theligandisrapidlymetabolized,withapproximately10%ofintacttracer remaining30minafterinjection.When 11C-PiBisusedasatreatmentendpointininterventionstudiesfor Alzheimer’sdisease(AD),aconcerniswhethertheclearanceofthetracerchangesfromonescantothenext, increasingwithinsubjectvariabilityinthePETsignal.SubjectsenrolledinADtrialsmaystartorstopmedications thatinhibitorinducexenobioticmetabolizingenzymessuchasthecytochromeP450(CYP)isozymes. Findings:WeconductedCYPphenotypinginrecombinantlyexpressedsystems,andinhumanlivermicrosomes,to evaluateCYPisozymecontributionstothemetabolismofPiB(carrier)andprofiledmicrosomalandhepatocyte incubationsformetabolites.ThemetabolismofPiBappearstobepolyzymic,withdirectconjugationviaUDP- glucuronosyltransferases(UGTs)alsooccurring. Conclusion:ItisunlikelythatCYPinhibitionorinductionwillsignificantlyinfluencetheclearanceof 11 C-PiB. Keywords:Amyloid,PittsburghcompoundB,Drugmetabolism,Hepaticclearance,P450phenotyping Findings Background A critical issue is the possible changes in clearance of thetracerasthiscouldaltertheinput functioninto the ThethioflavinTderivative, N-methyl-[11C]2-(40methyla- brain. Metabolism ofa tracerthat dependsprimarily on minophenyl)-6hydroxybenzothiazole(11C-PiB),hasbeen oneofthecytochromeP450(CYP)isoenzymescouldbe developed as a positron-emission tomography (PET) vulnerable to inhibition by particular medications. Sub- ligand for evaluating fibrillar β-amyloid (Aβ) in the jectsenrolledinADtrialsmaystartorstopanumberof human brain. Retention of 11C-PiB in the cortex corre- medication