Quantitative relationship between the octanolwater partition coefficient and the diffusion limitation of the exchange between adipose and blood 英文参考文献.docVIP

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Quantitative relationship between the octanolwater partition coefficient and the diffusion limitation of the exchange between adipose and blood 英文参考文献.doc

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Quantitative relationship between the octanolwater partition coefficient and the diffusion limitation of the exchange between adipose and blood 英文参考文献

LevittBMCClinicalPharmacology2010,10:1 /1472-6904/10/1 RESEARCH ARTICLE OpenAccess Quantitativerelationshipbetweentheoctanol/ waterpartitioncoefficientandthediffusion limitationoftheexchangebetweenadiposeand blood DavidGLevitt Abstract Background:Thegoalofphysiologicallybasedpharmacokinetics(PBPK)istopredictdrugkineticsfroman understandingoftheorgan/bloodexchange.Thestandardapproachistoassumethattheorganis“flowlimited” whichmeansthatthevenousbloodleavingtheorganequilibrateswiththewell-stirredtissuecompartment. Althoughthisassumptionisvalidformostsolutes,ithasbeenshowntobeincorrectforseveralveryhighlyfat solublecompoundswhichappeartobe“diffusionlimited”.Thispaperdescribesthephysicalbasisofthisadipose diffusionlimitationanditsquantitativedependenceontheblood/water(Kbld-wat)andoctanol/water(Kow )partition coefficient. Methods:Experimentalmeasurementsofthetimedependentratbloodandadiposeconcentrationfollowing eitherintravenousororalinputwereusedtoestimatethe“apparent”adiposeperfusionrate(FA)assumingthatthe tissueisflowlimited.ItisshownthattheratioofFA totheanatomicperfusionrate(F)providesameasureofthe diffusionlimitation.AquantitativerelationshipbetweenthisdiffusionlimitationandKbld-wat andKow isderived.This analysiswasappliedtopreviouslypublisheddata,includingtheOberget.al.measurementsoftheratplasmaand adiposetissueconcentrationfollowinganoraldoseofamixtureof13differentpolychlorinatedbiphenyls. Results:SolutesbecomediffusionlimitedatvaluesoflogKow greaterthanabout5.6,withtheadipose-blood exchangeratereducedbyafactorofabout30forasolutewithalogKow of7.36.Quantitatively,aplotofFA/F versusKow iswelldescribedassuminganadiposepermeability-surfaceareaproduct(PS)of750/min.ThisPS correspondstoa0.14micronaqueouslayerseparatingthewell-stirredbloodfromtheadiposelipid.Thisis approximatelyequaltothethicknessoftheratadiposecapillaryendothelium. Conclusions:Theseresultscanbeusedtoquantitatetheadipose-blooddiffusionlimitationasafunctionofKow . Thisisespeciall