酸枣仁油软胶囊的新药开发研究.ppt

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1、CHAPTER3Pharmacokinetics（bodyactsondrug）PHARMACOLOGICPRINCIPLES(sitesofaction)bindingfree(accumulation)freebindingdrugsposcim(plasma)Freedrugsbindingdrugsmetabolites(renal)excretionMetabolism(liver)absorptiondistributiondistributiondistributionpharma

2、cokineticsUndergoingofdrugsinbodytransformationoutofbodytransportperoralsubcutaneousintramuscularThemembraneswithporearecomposedoflipidsandproteinsinaratioof70:1.Theliquid-formdouble-deckofmembranesisformedfromlipidmolecules;Thespecialproteinsinserte

3、dintothedouble-deckarereceptors,enzymes,ionchannels,carriers……Ⅰ.Drugpermeationacrossmembranes1.membranepharmacokineticspermeationacrossmembranesfenestratedmembraneHighconcentrationLowoncentrationATPmembraneecto-Intra-lipiddiffusionporefiltrationcarri

4、erFacilitatedtransportActivetransportAdrugmoleculemovesfromasideofmembranerelativelyhighconcentrationtoanothersideoflowconcentrationwithoutrequiringenergy,untilanequilibriumhasbeenachievedonbothsidesofthemembrane.2.Passivetransportacrossmembranes(dow

5、nhill)highlowequilibriumpharmacokineticsLipiddiffusion;Filtration;Facilitatedtransportpermeationacrossmembranes…..…..…..…..…..…..…..…..…..…..…..…..…..…....…..…..…..…....NonionizedformIonizedform1)Lipiddiffusion(Simplediffusion)iontrappinglesspolarmo

6、leculespolarmoleculesThemostimportantmechanismofdrugtransportpharmacokineticspH(pKa)┐pKaispHwhenIonizedrateis50%permeationacrossmembranesmorelipidsolublelesslipidsolubleeasypermeationhardpermeationDrugmovementacrossmembranesisdrivenbyaconcentrationgr

7、adientaftersolutioninthelipidsofmembranes.k1k2k1[H+][A-]k1[H+][B]Ka＝──＝─────Ka＝──＝────k2[HA]k2[BH+][A][B]pKa＝pH－log───pKa＝pH－log───[HA][BH+][A-][B]pH－pKa＝log───pH－pKa＝log───[HA][BH+]HA(weakacids)B(weakbases)k1k1HAH+＋A-B＋H+BH+k2k2pharmacokineticsL

8、ipiddiffusion[A-][B]───＝10pH－pKa───＝10pH－pKa[HA][BH+]weakacidsweakbases★pH↑↓→[A-]↑↓★pH↑↓→[BH+]↓↑→ionization↑↓→ionization↓↑→lipidsolution↓↑→lipidsolution↑↓→permeation↓↑→permeation↑↓pharmacokinetics[A-][B]───＝10pH-pKa───＝10pH-pKa[HA][BH+]Lipiddiffusio