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PermeabilityWeAreDeterminedToServeYouBetter?Aug.18,2010PermeabilityIntroductiontoPermeabilityMechanismModificationStrategiestoImprovePermeabilityPredictionofPermeabilityPermeabilityFundamentalsDrugmoleculesencounterseveraldifferentmembranebarriersinlivingsystems,forexample,GIepithelialcells,bloodcapillarywall,hepatocytemembrane,glomerulus,organbarriers,thetargetcellmembrane.Components:Hydrophilicpolarheadgroup;Hydrophobicfattyacidchainofphospholipids;Othercomponents:cholesterol,transmembraneproteins(channels,transporters,receptors)StructureofsomecommonphospholipidsPermeabilityMechanismFivemajorpermeabilitymechanism:

PassivediffusionActiveuptake

EndocytosisEfflux

Paracellular2

Passivediffusionpermeability

ThemostimportantpermeabilitymechanismfordrugdiscoveryDrivenbyaconcentrationgradient,withthenetmovementofmoleculesfromtheareaofhigherconcentrationtotheareaoflowerconcentration.Permeabilityismuchhigherformorelipophilicmoleculesthanforpolarmolecules.Neutralmoleculesaremuchmorepermeablethantheirchargedforms.pHandpKaplayimportantrolesinpassivediffusion.ThepassivediffusionofacidsismuchhigheratlowpH,whereasthepassivediffusionofbasesislowatlowpH.ThepassivediffusionpermeabilityofneutralmoleculesisunaffectedbypH.CaseofPassivediffusionpermeability3OtherroutesofpermeabilityEndocytosisPermeability:anotherrouteofpermeability-onlyminorinterestforsmallmolecule.Activeuptakepermeability:boundtoatransmembraneproteinandmovesthroughthemembrane.Itoftenoccursagainsttheconcentrationgradient.ParacellularPermeability:smallandpolarmoleculespassbetweentheepithelialcellsthrough“pores”orchannelsthatareapproximately8Ainsize.EffluxPermeability:theactivetransportofcompoundsfrominsidethecellormembranebackintothelumenalspace,forexample,P-glycoprotein(Pgp)andbreastcancerresistanceprotein(BCRP)well-knowneffluxtransporters.

4Combinedpermeability56

Twoofthesefactors:bioavailabilityandcell-basedbiologicalactivityassays.DrugabsorptionintheGItractafteroraladministrationdependsheavilyonpermeability.Permeabilitycanlimittheactivityofcompoundsincell-basedassays.PermeabilityEffectsPermeabilityEffectoncell-basedassays7PermeabilityStructureModificationStrategiesFormulationsarenoteffectiveinfixingpermeability.Severalstrategiesforimprovingpermeability:reduceionizability,increaselipophilicity,reducepolarity,orreducehydrogenbonddonorsoracceptors8IonizableGrouptonon-ionizableGroup9AddLipophilicity10IsostericReplacementofPolarGroups11EsterifyCarboxylicAcid12ReduceHydrogenBondingandPolarity13ReduceSize14AddNonpolarSideChain15Prodrug16PermeabilityMethodInsilicomethodsareavailableforcalculatinginvivioandinvitropermeability.InvitroPermeabilityMethodsImmobilizedartificialmembrane(IAM)HPLCCelllayerParallelartificialmembranepermeabilityassay(PAMPA)IAMHPLC:ThechromatographiccapacityfactorkincreaseswithIncreasingaffinityforthephospholipidphase.ThecorrelationtopermeabilitymaybebetterthanLogD,lesspredictivethansomeothermethods.Requireverylittlematerial,imputitynotinterferewithpredictionInvitroPermeabilityMethodsCelllayerMethodforPermeabilityCaco-2,MDCKandPAMPAComparis

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