药代动力学.ppt

Pharmacokinetics药代动力学,LinYuanPh.DProf,学习要点：基本要求：该部分的学习目的为掌握药理学的基本概念；熟悉与药理学基本概念相关的知识；了解药动学与药效学的相关公式与知识。延伸要求：将总论中的概念与相关生理生化知识各论中药物的效应联系起来，该种联系贯穿药理学及其它基础与临床医学知识学习的始终。学习方法：注意各种概念间的联系：如药物的跨膜转运与机体对药物的吸收分布及排泄过程有关与药物的理化性质有关也与机体的状态有关。,Q-Describewhatispharmacokinetics?Thestudyofthedynamicchangesofdrugsinthebody,thatis,theprocessofabsorption,distribution,biotransformation(metabolism)andexcretionofdrugsinthebody.阐明药物在人体内的吸收、分布、代.谢和排泄的动态变化规律即药物在体内（1）所经历的过程（吸收、分布、代.谢和排泄跨膜转运）；（2）变化的方式与结果；（3）影响因素（药物与机体两方面）。,药动学的特征:Likea“journey”ofdruginthebody-Howthe“journey”ofadrugisproceed:absorption,distribution,biotransformationandexcretion.Whathappenstodrug:looseactivity,increaseionicsolubility.Whatfactorsinfluencethejourneyofadruginthebody?药动学在科研方面的应用:Quantitativedescriptionofthetimecourseofdrugandmetaboliteconcentrationsinplasma,tissueandurine.药动学的临床应用:Guidefordrugchoiceandadjustmentofdosage,Distribution(tissue),Drug,Plasma,Bio-transformationliver,Excretion,kidney,药物在体内的动态过程-1,Absorption,药物在体内的动态过程-2,为什么A代表药动学，B代表药效学；C代表两者？,Q-Whatisdrugtrans-membranetransport（跨膜转运）?Toachievetherapeuticeffects,drugscrossvariousbiologicalmembranes,by被动转运passivetransportor/and主动转运（activetransport）.Drugtrans-membranetransportareinvolvedinAbsorption,distribution,andExcretion.CanyoudescribethatwhatdependsonforaAdrugtocrosscellmembranes?Aretheresomethingsharedincommon?UnderstandFactorsinfluencestheprocess.molecularsize(b)needsnoenergy;(c)influencedbylipidsolubilityofdrugandbydifferencesinpHacrossthemembrane.Difference:Facilitateddiffusion(a)needscarrier;(b)hasdrugtransportsaturation;(c)hasdrugcompetitionandselectivity.Simplediffusion,FiltrationNocarrierneeded.,2.Activetransport（主动转运）Activetransporthasfollowingfeatures:(a)needsspecialcarriers;(b)Requirementofenergyconsumption.(c)Drugscantransportfromlowtohighconcentration.(d)presencetransportsaturationand(e)presenceofcompetitiveinhibition.AlternativeclassificationCarriermediatedtransport（载体转运）:ActivetransportandFacilitatedtransport（主动转运与易化转运）Non-carriermediatedtransport:Simplediffusion,andFiltration（非载体转运）,carrier-mediatedtransport:Movementwhichoccursacrossmembranes,suchasthebloodbrainbarrierandthegastrointestinalmucosa.Themechanismisalsocharacterizedby(1)beingsaturable;(2)competitiveinhibitionoccurs.Therearetwoformsofcarrier-mediatedtransport,activetransportandfacilitateddiffusion.Therapidtransferofdrugmetabolitesintourineisbyactivetransport.Entryofglucoseintomostcellsisbyfacilitateddiffusionbutitspassageacrossthegastrointestinalmucosaisbyactivetransport.,Passiveandactivetransport-2,II.TheprocessofdrugtransportQ-Whatisdrugabsorption（吸收）?Doallkindsofadministrationpossessabsorption?MovementofdrugmoleculesfromthesiteofadministrationtothesystemiccirculationbypassingthecellmembranebarrieriscalledAbsorption.DrugadministrationOraladministration,(mostpopular,advantage:convenient,economical,andofefficiencyforabsorption).Disadvantage:irritationtogastrointestinalmucosa,irregularityinabsorption,andFirstpasseffect（metabolism,首关效应）,whichmeansthatorallyadministereddrugsaremetabolizedinintestinalflora,andliverwhenabsorbedfromhepaticportalsystembeforetheyfirstgainaccesstothegeneralcirculation.首关效应：口服药物经肠道、肝脏门脉系统进入体循环前，被肠道菌群及肝药酶代谢，使进入体循环的药量减少，这样一种现象叫做首关效应。,首关效应,（Hepatoenteralcirculation,肝肠循环）:Drugisexcretedintothesmall,intestinebybilesecretion,andabsorbedthereagainiscalledhepatoenteralcirculation.,PlotofCpversusTimeforAandB;BhavingSlowerAbsorption,Doabsorptioninvolveinanytypeofadministration?,TheimportanceofHepaticFirst-Passeffect(Metabolism),AffectsorallyadministereddrugsMetabolismofdruginliverbeforedrugreachessystemiccirculationDrugabsorbedintoportalcirculation,mustpassthroughlivertoreachsystemiccirculationMayreducebioavailability（生物利用度）ofdrug。Firstpasseffectisalsoatypeofbiotransformation,i.e.,theeliminationofasubstance,e.g.,adrugintheliverafterabsorptionfromtheintestineandbeforeitreachesthesystemiccirculation.,Sublingual（舌下）Drugsabsorbedsublinguallymeansdrugsareabsorbedthroughmouththinmucosaanddonothavefirstpasseffectingastro-intestine.硝酸甘油（Nitroglycerin）InjectionIntravenous(i.v.):directtogeneralcirculationandismostfastway.Theotherinjectioninclude:subcutaneous,intra-muscular.Rectalmucosa（直肠粘膜）Advantage:Avoidvomiting,nofirstpasseffect,usedwhenpatientisun-coconscious.Disadvantage:rectalabsorptionisoftenirregularandincomplete.,IV(静脉注射injectionandinfusion)doesnotneedabsorption.Localanesthesia:drugabsorptionisthewayofelimination.Drugsystemiceffectviadrugabsorbedintogeneralcirculation.,Q-WhatdoesbioavailabilitymeanBioavailabilityreferstotheextenttowhichadrugreachesitssiteofaction.(systemic，local)生物利用度与药物能够达到作用的靶点有关。,F,进入体循环的药量（A）,用药剂量（D）,100%,Dosereachesthesystemiccirculation,Dose(administered)=ivadministration,F,100%,定义与公式见的关系，是否可用公式代替定义？,Bioavailabilityisusedtodescribethefractionofanadministereddoseofunchangeddrugthatreachesthesystemiccirculation,oneoftheprincipalpharmacokineticpropertiesofdrugs.Bydefinition,whenamedicationisadministeredintravenously,itsbioavailabilityis100%.1However,whenamedicationisadministeredviaotherroutes(suchasorally),itsbioavailabilitydecreases(duetoincompleteabsorptionandfirst-passmetabolism)ormayvaryfrompatienttopatient(duetointer-individualvariation).,Absolutebioavailability(绝对生物利用度）isthefractionofthedrugabsorbedthroughnon-intravenousadministrationcomparedwiththecorrespondingintravenousadministrationofthesamedrug,Absolutebioavailability（绝对F）：,F,AUCpo,AUCIV,100%,（Relativebioavailability相对生物利用度）（相对F）：,F,AUCtested,AUCstandard,100%,AUC(iv),AUC(po),PlotofCpversusTimeafterIVandIMAdministration.NOTE:AUCsarealmostsame.,FoodEffectsonBioavailability对于药物吸收，食物可以增加、降低或不影响药物的吸收Foodmayincrease,decrease,orhavenoeffectontherateand/ortheextentofabsorption。Mayaffectrateandextentindependently.FoodEffectsGImotilityandalsocanincreasesolubilizationofdrugsChangemaydependoncontentofmealFoodmaymitigate（decrease)nauseaVomitingtendstodecreasebioavailabilityTimeofdosewithrespecttofood。（根据不同食物，选择不同服药时间）。,Bioequivalence(生物等效性)meansthatonebrandordosageformofadrugorsupplementisequivalenttoareferencebrandordosageformofthesamedrugintermsofbioavailabilityparametersmeasuredviainvivotestinginhumansubjects.Bio-equivalenceofhumandrugsmustbedeterminedinhumansviaestablishedmeasuresofbioavailability.,两个药学等同的药品，若它们所含的有效成分的生物利用度无显著差别，则称为生物等效。,AUCAreaundertheconcentration-timecurveCmaxMaximumconcentrationAdifferenceofgreaterthan20%inCmaxortheAUCrepresentsasignificantdifferencebetweenthestudyandreferencecompoundsTmaxTimetomaximumconcentration,StudyCompoundReferenceCompound,Time,Concentration,Cmax,Tmax,AUC,为了检验药物制剂与参比品在吸收利用的程度上是否一致，保证药物制剂的安全可靠性，特地规定药物制剂的AUC、Tmax及Cmax应在参比品的80120%范围内，称为“等效性检验”。其中AUC等效反映了吸收数量相近，Tmax等效说明吸收速率相近，Cmax则与用药安全性有关。,Testofbioequivalence(生物等效性检验),Q-Whatisdrugdistribution（分布）Distributionistheprocessbywhichadrugdiffusesoristransferredfromintravascularspacetoextra-vascularspace(bodytissues).Inthesimplestofterms,adrugsvolumeofdistributionisthatvolumeofbodilyfluidintowhichadrugdoseisdissolved.Therefore,ifweknowthedosethatwasgiven,andwecanmeasuretheserumlevel(concentration),thenwecancalculateavolume:(药物自血液系统进入组织的过程)Volumeofdistribution=Dose/drugconcentration;Vd=A/C,Vd(apparentvolumeofdistribution，表观分布常数）A(totalamountdrugmg)C(plasmaconcentrationofdrug)Vd=A/C（C血浆药物浓度）(Vd)istheamountofdruginthebodydividedbytheconcentrationintheblood.Drugsthatarehighlylipidsoluble,suchasdigoxin,haveaveryhighvolumeofdistribution(500litres).Drugswhicharelipidinsoluble,suchasneuromuscularblockers,remainintheblood,andhavealowVd.（表观分布常数说明药物在体内分布范围，而不是实际分布体积）.,Vd=A(dose)/C(concentration)SystemicdistributionPlasma3L（血浆）Extra-cellular15L（细胞外液）Intra-cellular40L（细胞内液）BindingtobloodproteinsUnevendistributioninbodyorgansDepositioninfattissueDepositioninliver/kidneysDepositionintargetorganInternalbarriers-Bloodbrainbarrier/Placenta,Q-Describefactorsinfluencingdrugdistribution1.bodyfactor(1)组织屏障Tissuebarrier(a)血脑屏障Bloodbrainbarrier,胎盘屏障placentabarrier,gastrointestinalmucosa,epithelialbarrierofskinorbladder.(Thebarriersbetweenbraincellandblood,braincellandcerebrospinalfluid,aswellasbloodandcerebrospinalfluidarecalledbloodbrainbarrier.Nowhereinthebodyistheremoreneedforhomeostasisthaninthebrain.Bloodbrainbarrierprotectsbrainfromcirculatingtoxin,highMWorhighlywatersolubledrugs,e.g.,quaternaryamines,andharmfulsolutes.Ifneeded,lipidsolubleagentisavailable.),Over100yearsago,theconceptofthebloodbrainbarrierwasfirstintroducedbyPaulEhrlich.Hefoundthatintravenousinjectionofdyesintothebloodstreamstainedallthetissuesinmostorgansexceptbrainandspinalcord。Theresultssuggestthattheremustbeabarrierbetweenbrainandbody(b)Placentabarrier（胎盘屏障）Mostdrugscancrosstheplacentaandenterthebreastmilk.Thedifferenceisthelimitedmaternalbloodflowingintoplacenta,thefastesttimefordrugequilibrationbetweenmotherandfetusisintheorderof10-15min.,Drugsharmfultofetusshouldnotbegiventopregnantwoman.孕妇应避免服用对胎儿有害的药物(2)Absorbingsurface(3)Bloodflow(4)EnvironmentalpH(5)Diseasestates,2.DrugfactorsIncluding:Tabletformulation;lipid/watersolubility;pH;Concentration,Drugcanbedividedintoweakacidandweakbase(弱酸性药物与弱碱性药物)Q-Describetheformofweakacidinacidicandbasicsolution.Q-Describetheformofweakbaseinacidicandbasicsolution.弱酸性药物在酸性条件下呈分子状态弱碱性药物在碱性条件下呈分子状态推论：弱酸性药物在碱性条件下呈离子状态弱碱性药物在酸性条件下呈离子状态分子状态-脂溶性强-易被吸收离子状态-水溶性强-易被排泄,弱酸（HA）弱碱（B）的分子与离子状态,WeakAcids,Release/DonateH+,HAH+A-,WeakBases,Bind/AcceptH+,H+B,HB+,HAH+A-,H+B,HB+,Xisanacidicdrug.(a)Inthestomachwillitexistmostlyinionizedornon-ionizedform?(b)WhereisXmoreeasilyabsorbed,stomachorintestine?(c)WhereisXmostlyabsorbed,stomachorintestine?,Ionizedform(charged),A-,Un-ionizedform(uncharged),HA,HA,LipidBilayer,弱酸与弱碱在细胞膜内外分布,Ionizedform,A-,Non-Ionizedform,HA,B,HB+,IntracellularpHi=7.0,Plasma,ExtracellularpHe=7.4,Non-Ionizedform,Ionizedform,Describewhydruglipid/watersolubilityinfluencedrugabsorption/distribution/excretion?（为什么药物的脂/水溶性影响药物的吸收/分布/排泄）Drugdiffusionacrossmembraneisaffectedbythephysicochemicalpropertiesofdrugssuchasmolecularweight,polarity,lipid/watersolubility.Mostdrugsareweakelectrolytes,andpresenceinbothunionizedandionizedforms.Theunionizedformhasstrongerlipid-solubilityandiseasiertodiffuseacrossthemembraneduetothelipoidcharacteristicsofthebiologicalmembrane.Theionizedformwhichhasstrongerpolarityisdifficulttodiffuseacrossthemembraneduetothewatersolubilityandiseasiertobeexcretedfromkidney.,LipidBilayer,Small,uncharged,Large,uncharged,Smallchargedions,H2O,urea,CO2,O2,N2,GlucoseSucrose,H+,Na+,K+,Ca2+,Cl-,HCO3-,DENIED!,DENIED!,Swoosh!,跨膜转运,WeakacidpHpKa=lg(A-/HA)AcidicdrugsarebestabsorbedfromacidicenvironmentsWeakbasepKa-pH=lg(BH+/B)Basicdrugsarebestabsorbedfrombasicenvironments,numerator,Denominator,弱酸弱碱解离度与环境pH的关系,弱酸弱碱在不同pH情况下存在方式，怎样计算他们的pKa？,MainlyHAandBH+,MainlyA-andB,例如：某酸性药物pKa=7,计算其在pH=9,及pH=5时的吸收/排泄情况pH=9的情况pHpKa=lg(A-/HA)=97=2=lg(100/1)易排泄/难吸收。pH=5的情况pHpKa=lg(A-/HA)=57=-2=lg(1/100)难排泄/易吸收。小结：酸性药物在酸性环境下容易被吸收。碱性药物在碱性环境下容易被吸收。,AdrugpKa=7,calculatetheconditionofreabsorption/excretionpH=9,及pH=5（1）pH=9的情况pKapH=lg(BH+/B)=79=-2=lg(1/100)难排泄/易吸收。（2）pH=5的情况pKapH=lg(BH+/B)=75=2=lg(100/1)易排泄/难吸收。,Q-HowtocalculatethepKaofadrugpKaisthepHatwhichtheconcentrationofionizedandun-ionizeddrugissame(50%each)forbothweakacidicandbasicdrugsForbothweakacidicandbasicdrugs,e.g.,theirpKamaybe3.1,4.6,5.3,7.4,8.6,9.2etc,atwhichthedrugconcentrationofionizedandun-ionizedformissame,.PleasedescribetheimportanceofdrugPlasmaProteinbinding(DPPB)（药物-血浆蛋白结合的重要性）Onlyfreedrughaspharmacologicaleffects,Reductionofdrugdistribution,biotrans-formationandexcretionDrug-plasmaproteinbindingisreversibleandisservedasadrugreservoirAcompetitionsiteformanydifferentdrugsDPPBactasatransportmechanismforthedrugtothesiteofactionorelimination.(relatedtodrugdistribution),WhereisDrugstoredinthebody,(1)Plasmareservoir(2)Cellular(tissue)Reservoir(3)FatReservoir(4)BoneReservoir,BIOTRANSFORMATION1,DefinitionBiotransformationisanenzyme-mediatedtransformationofonechemicalintoanotherwithinthelivingorganism,e.g.,chemicaltransformationsofforeigncompoundsincludingdrugs.（在生物体内，由酶介导的，将外源性物质进行的化学转化，从一种物质转化为另一种物质）TheplaceofBiotransformation:liver(main);smallintestine,lung,andkidney,etc.(主要转化部位：肝脏),SignificanceEvolutionhasprovideduswithmechanismstoeliminatetheseforeigncompoundsfromourinternalenvironment.Manydrugsarehighlylipid-soluble,unionizedatnormalpH,areeithernotreadilyfilteredattheglomerulusorareeffectivelyre-absorpedinthekidney.theyarebio-transformedintoaninactive,morecharged,water-solublemetabolitetoexcrete.,BIOTRANSFORMATION2,Consequenceofbiotransformation（生物转化的结果）(1)Inactivationandmorewatersoluble(most),e.g.,acetylsalicylicacid(aspirin)aceticacid+salicylate.(2)Activecompoundactivecompound,e.g.,diazepam（地西泮）oxazepam（奥沙西泮）.(3)Activation,e.g.,L-dopa（左旋多巴）dopamine.（多巴胺）Thedifferencebetweenbiotransformationandmetabolismmetabolismmeansbreakdownandinactivation.However,biotransformationincludenotonlybreakdownandinactivation”butalsosyntheticreactions.,BiotransformationReactions(BR),BRincludephaseIandphaseIIreactions.FeaturesofphaseIreactions（I相反应的特征）A.Converttheparentcompoundtoamorepolarmetabolitebyintroducingorbyunmaskingafunctionalgroupsuchasan-OH,-SH,orNH2group.PhaseIreactionsincludeoxidation,reductionandhydrolysis.B.ThemetabolitesresultingfromaphaseIreactioncanbeinactive,lessactive,oroccasionallymoreactivethantheparentcompound.C.PhaseIReactionsdonotrequireenergy.PHASEIREACTIONS,PHASEIREACTIONS,ReactionsClass,StructuralChange,DrugSubstrates,OxidationsP450-Aromatichydroxylations,Propranolol,phenobarbital,phenytoin,amphetamine,warfarin,-Aliphatichydroxylations,Amobarbital,pentobarbital,chlorpropamide,ibuprofen,digitoxin,RCH2CH3,RCH2CH2OH,RCH2CH3,RCHCH3,OH,PHASEIREACTIONS,ReactionsClass,StructuralChange,DrugSubstrates,-Oxidativedealkylation-O-dealkylation-S-dealkylation,Codeine,p-nitroanisole6-methylthiopurineAniline,chlorphentermine2-acetylamino-fluorene,acetaminophen,ROCH3,ROH+CH2O,RSCH3,RSH+CH2O,N-oxidation1amines2amines,RNH2,RNHOH,R1,NH,R2,R1,NOH,R2,Acetaminophen(APAP),PAPS,PAP,Phenolsulfo-transferase,APAPSulfate,UDP-glucuronosyl-transferase,UDP,UDPGA,APAPGlucuronide,GSH,Glutathioneconjugate,N-acetyl-p-benzoquinoneimine(toxic),P450,PHS,PhaseII(SyntheticorConjugation结合)ReactionsA.usuallyrequireenergy,nearlyalwaysinactivatesparentcompound,withfewexception.B.PhaseIIreactionsareconjugationreactions.Inhumans,glucuronidationisthemostimportantone.C.TheconjugationreactionsfrequentlyoccurafteraninitialPhaseIreaction.Thereactionistomakethedrugmorepolar,andmorereadilyexcreted.,PhaseIandIIreactions,CytochromeP450enzymes细胞色素P450酶,Theendoplasmicreticulum(内质网，ER)membranesoflivercellscontaincytochromeP450enzymes(mixedfunctionoxidases（混合功能氧化酶）,monooxygenases,hepaticdrugmetabolizingenzyme(HDME)（肝脏药物代谢酶).Reaction:Theenzymesrequiresbothareducingagent(NADPH)andmolecularoxygen,andthekeystepistoinsertanO2intothesubstrate.,CharacteristicsofHDME（肝药酶作用的特征）Non-selective:（非选择性）Alldrugs(foreignsubstance)canbebiotransformed(detoxification).Inducible(可诱导）increaseactivitiesofHDME)Subtype:18differentformsofcytochromeP450(CYP)identifiedinhumans;eachtheproductofaseparategene.ImportantcytochromeP450sinhumansare:CYP3A,CYP1A2,CYP2C,CYP2D6,CYP2E1.CYPfamilyofenzymesimportanttodrugdegradationinliverandinsmallintestine.,Whydrugmetabolizingenzymeisimportantfordrugtherapy?SixtypercentoforaldrugsmetabolizedprimarilybyaspecificformofHDME-CYP3AFortypercentofdrugcandidatesfailbecauseoforalbioavailabilityproblemsOvercomingthefirstpasseffectmayresultinhighoraldosesorresortingtoIVadministrationCYP3Ainhibitorsboostoralbioavailability,Geneticdifference(mostimportant):geneticdifferencesinpeoplesabilitiestometabolizedrugsthroughcertainmetabolicpathwaysEnvironmentalfactors:Exposuretoenvironmentalpollutantske=0.693/t1/2(h),QVd(Theapparentvolumeofdi