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Utility of drug de
Utility of drug de
DRUGMETABOLISMANDDISPOSITIONVol.40,No.8Copyright(C)2012byTheAmericanSocietyforPharmacologyandExperimentalTherapeutics6DMD40:,2012
UtilityofDrugDepletion-TimeProfilesinIsolatedHepatocytesfor
AccessingHepaticUptakeClearance:IdentifyingRate-Limiting
StepsandRoleofPassiveProcesses
EmilieJigorel1andJ.BrianHouston
CentreforAppliedPharmacokineticResearch,SchoolofPharmacyandPharmaceuticalSciences,UniversityofManchester,
Manchester,UnitedKingdom
ReceivedMarch16,2012;acceptedMay16,2012ABSTRACT:
Drugdepletion-timeprofilesinisolatedhepatocytes,aswellaseliminationwithinthehepatocyte,whichisdistinctfromthetimemicrosomes,havebecomeastandardmethodofassessinghe-profileinaconventionalincubation,andshowhigherclearances.paticmetabolicclearanceinvitro.ThereisapreviouslydescribedThefourothercompounds(clarithromycin,saquinavir,erythromy-adaptationofthedepletionapproachtoallowdeterminationofcin,andrepaglinide)showidenticaldepletion-timeprofiles(andhepaticuptakebytransportersinadditiontometabolism(Drugclearances)inbothsetsofincubations.Whetherornotthebipha-MetabDispos35:859–865,2007).Dualincubationsareperformedsicnature(andhigherclearance)isevident,indicatingtransporterwhereonesetofincubationsundergoconventionalmethodology,activityforaparticulardrug,appearstobedependentonitspas-whereasforthesecondset,http://www.wendangku.net/doc/5df.html ingtheparameterKputoreflecttherelativedeterminationofdruglossfromthemedia.Theutilityofthisdualimportanceofhepatictransportersversuspassivediffusion,aincubationapproachhasbeenassessedusingeightdrugs(ator-valueof10wasidentifiedasacutoffforwhetherthebiphasicvastatin,clarithromycin,erythromycin,fexofenadine,pitavastatin,thosecompoundsinexcessof10showthisrepaglinide,rosuvastatin,andsaquinavir)witharangeofactivecharacteristicclearly.Thereappearstobenorelationshipbetweenuptake,passivepermeability,cellbinding,andmetaboliccharac-thepresenceofthebiphasicnatureandanyotherparameter,teristics.Fourofthesecompounds(fexofenadine,rosuvastatin,includingcellularbinding,extentofmetabolism,orthemagnitudepitavastatin,andatorvastatin)showabiphasictimeprofilewhenofactiveuptake.
assessingdruglossfrommediaindicativeofhepaticuptakebefore
Introductionofthisprocess,inawayanalogoustoaninvivopharmacokinetic
Theuseofisolatedhepatocytes,eitherinsuspensionorasastudy.Thepopularityofinvitrosystemstomakequantitativepredic-monolayer,hasallowedmanyaspectsofqualitativeandquantitativetionsofinvivoclearancehasledtosimilarinvestigationsusingdrugmetabolismtobeassessed(Hewittetal.,2007;Soarsetal.,hepaticmicrosomes(Obach2001;Rileyetal.,2005).Thissubstrate2007a).Investigationsperformedasearlyasthemid1970s(Inabaetdepletionapproachiswidelyusedbecauseformalkineticcharacter-al.,1975;YihandvanRossum,1977)demonstratedtheuseoftheizationandmetabolitequantificationarenotrequired,allowingthesubstratedepletion-timeprofilewithinanincubationofisolatedhepa-rapidscreeningofcompounds.
tocytestoestimateclearanceandtocharacterizethenonlinearnatureThebasisofpredictinginvivoclearancevaluesfrominvitro
kineticparametersistheuseofMichaelis-Mentenkineticsandexpe-
rientialdataobtainedunderinitialrateconditions(Houston,1994).
ThisworkwassupportedbyaconsortiumofpharmaceuticalcompaniesForanumberofdrugswithsimplemetabolicpathways,ithasbeen(GlaxoSmithKline,Lilly,Pfizer,andServier)withintheCentreofAppliedPharma-demonstratedthatdrugdepletionandmetaboliteformationcanpro-cokineticResearchattheUniversityofManchester.
1Currentaffiliation:UCBPharmaSA,DrugMetabolismandPharmacokinetics,videequivalentclearanceterms(JonesandHouston,2004;Sjo¨grenet
Brainel’Alleud,Belgium.al.,2009;Stringeretal.,2009).However,JonesandHouston(2004)
Thisworkwaspreviouslypublishedinpartinthefollowingpublication:JigorelhavealsoindicatedtheimportanceofenzymestabilityforlongerEandHoustonJB(2009)Involvementofdruguptakeinhepaticclearance.Drugincubationtimesbecauseinstabilitymaygeneratebiphasicdepletion-MetabRev41(Suppl1):66.timeprofiles.Thedrugdepletionmethodassumesthattheconcentra-Article,publicationdate,andcitationinformationcanbefoundattionsofdruginmediaandcellsarethesame,whichmaynotbetruehttp://www.wendangku.net/doc/5df.html .becauseoftransporterproteinactivity.Themostcommonapproachtohttp://www.wendangku.net/doc/5df.html /10.1124/dmd.112.045732.measurehepaticuptakeisanalogoustotheMichaelis-Mentenap-ABBREVIATIONS:CLactive,cleCLmet,cCLobs,observedinvitroclearance(eitherbyuptakeorbymetabolism);CLuptake,totaluptakeclearancebyactivfucell,fractionofunbounkdep,initialdKptotal,tissue-to-mediumtotaldrKpu,hepatocyte-to-mediumunbounddrOATP,organicaniontrPdiff,paLC-MS/MS,liquidchromatography-tandemmassspectrometry.
1596Downloaded from http://www.wendangku.net/doc/5df.html
at Central South Univ on July 5, 2014
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( P & 0 01) Conclusion T he breast cancer ste m ce lls can in crease the ir drug resistance by enhancing the expressio n of BCRP, w hich is ...关键词: miR-181 乳腺 癌耐药 ; BCRP The Targeted Inhibition of BCRP by MiR-181a Reverses Breast Cancer Cells Drug Resistancei JiashuDZhou MingyiJiao... BCRP_ABCG2的结构功能及相关抑制剂研究_能源/化工...研究发现 多重耐药菌(multi-drug resistance,MDR)...[35] de Bruin M, Miyake K, Litman T, et ...Very recently, we reported that ge?tinib reverses BCRP-mediated drug ...De Bruin M, Miyake K, Litman T, Robey R, Bates SE (1999) Reversal ...Hua et al. OATP1B1 and BCRP Gene Mutation Table 1 Drug uptake ...&G, c.463C&A, and c.521T&C polymorphisms that resulted in the de?...As controls in each experiment, the drug-sensitive human BCRP, MDR1, MRP...No. patients Expression level Age Expression in relapsed vs de novo AML ...BCRP has been demonstrated to be an important mediator of drugdrug ...(Ferrante et al., 1991; de Jong et al., 2004; Han et al., 2007; ... Breast cancer resistance protein molecular target for anticancer drug ...de bonds. To test for possible dominant-negative inhibition of the BCRP ... drug resistance, heme ■ Abstract The protein variously named ABCG2/BCRP/MXR/ABCP is a recently described ATP-binding cassette (ABC) transporter ... 上传我的文档
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