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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)andexcretionofdrugsint

hebody.•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”ofdr

uginthebody---Howthe“journey”ofadrugisproceed:absorption,distribution,biotransformationandexcretion.•Whathappenstodrug:looseactivity,increase

ionicsolubility.•Whatfactorsinfluencethejourneyofadruginthebody?•药动学在科研方面的应用:Quantitativedescriptionoftheti

mecourseofdrugandmetaboliteconcentrationsinplasma,tissueandurine.•药动学的临床应用:GuidefordrugchoiceandadjustmentofdosageDistribution(tissue)DrugP

lasmaBio-transformationliverExcretion,kidney药物在体内的动态过程-1Absorption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-membranetransportare

involvedinAbsorption,distribution,andExcretion.•CanyoudescribethatwhatdependsonforaAdrugtocrosscellmembranes?•Are

theresomethingsharedincommon?UnderstandFactorsinfluencestheprocess.1.molecularsize&shape2.solubilityatsightofabsorption3.ionisation4.lipi

dsolubilityFeatureandimportanceofPassivetransport（被动转运）(a)Themajorityofdrugsaretransportedbypassivetransport：Simplediffusion,Filtration，an

dsomebyFacilitateddiffusion(transport).Commonfeatures:(a)transportfromhightolowconcentration,anddependsonconcentrationgradient;(b)needsnoenergy;

(c)influencedbylipidsolubilityofdrugandbydifferencesinpHacrossthemembrane.Difference:Facilitateddiffusion(a)needscarrier;(b)hasdrugtransportsat

uration;(c)hasdrugcompetitionandselectivity.Simplediffusion,FiltrationNocarrierneeded.2.Activetransport（主动转运）Activetransporthasfollowingfeatures

:(a)needsspecialcarriers;(b)Requirementofenergyconsumption.(c)Drugscantransportfromlowtohighconcentration.(d)presencetransportsaturat

ionand(e)presenceofcompetitiveinhibition.AlternativeclassificationCarriermediatedtransport（载体转运）:Activetransp

ortandFacilitatedtransport（主动转运与易化转运）Non-carriermediatedtransport:Simplediffusion,andFiltration（非载体转运）•carrier-me

diatedtransport:Movementwhichoccursacrossmembranes,suchastheblood–brainbarrierandthegastrointestinalmucosa.Themechanismisalsocharacter

izedby(1)beingsaturable;(2)competitiveinhibitionoccurs.Therearetwoformsofcarrier-mediatedtransport,activetransportandf

acilitateddiffusion.Therapidtransferofdrugmetabolitesintourineisbyactivetransport.Entryofglucoseintomo

stcellsisbyfacilitateddiffusionbutitspassageacrossthegastrointestinalmucosaisbyactivetransport.Passiveandactivetransport-2II.T

heprocessofdrugtransport•Q-Whatisdrugabsorption（吸收）?Doallkindsofadministrationpossessabsorption?Movementofdrugmoleculesfromthes

iteofadministrationtothesystemiccirculationbypassingthecellmembranebarrieriscalledAbsorption.•DrugadministrationOraladministration,(mostp

opular,advantage:convenient,economical,andofefficiencyforabsorption).Disadvantage:irritationtogastrointestinalmucosa,irregularityinabsorpt

ion,andFirstpasseffect（metabolism,首关效应）,whichmeansthatorallyadministereddrugsaremetabolizedinintestinalflora,andliverwhena

bsorbedfromhepaticportalsystembeforetheyfirstgainaccesstothegeneralcirculation.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,andabsorbedthereagainiscalledhepatoent

eralcirculation.PlotofCpversusTimeforAandB;BhavingSlowerAbsorptionDoabsorptioninvolveinanytypeofadministration?TheimportanceofHepatic‘First-Pa

ss’effect(Metabolism)•Affectsorallyadministereddrugs•Metabolismofdruginliverbeforedrugreachessystemiccirculation•Drugabsorbedint

oportalcirculation,mustpassthroughlivertoreachsystemiccirculation•Mayreducebioavailability（生物利用度）ofdrug。•Firstpasseffectisal

soatypeofbiotransformation,i.e.,theeliminationofasubstance,e.g.,adrugintheliverafterabsorptionfromtheintestineandbeforeitreachesthesystemiccir

culation.•Sublingual（舌下）Drugsabsorbedsublinguallymeansdrugsareabsorbedthroughmouththinmucosaanddonothavefirst

passeffectingastro-intestine.硝酸甘油（Nitroglycerin）•InjectionIntravenous(i.v.):directtogeneralcirculationandismostfastway.Theotherinjectionincl

ude:subcutaneous,intra-muscular.•Rectalmucosa（直肠粘膜）Advantage:Avoidvomiting,nofirstpasseffect,usedwhenpatientisun-coconscious.Disadvantage:re

ctalabsorptionisoftenirregularandincomplete.•IV(静脉注射injectionandinfusion)doesnotneedabsorption.•Localanesthesia:drugabsorptionisthewayofelimination.•

Drugsystemiceffectviadrugabsorbedintogeneralcirculation.Q-WhatdoesbioavailabilitymeanBioavailabilityreferstotheextenttowhichadrugreachesits

siteofaction.(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%DosereachesthesystemiccirculationDose(admini

stered)=ivadministrationF＝×100%定义与公式见的关系，是否可用公式代替定义？•Bioavailabilityisusedtodescribethefractionofanadministereddoseofunchang

eddrugthatreachesthesystemiccirculation,oneoftheprincipalpharmacokineticpropertiesofdrugs.Bydefinition,whenamedicatio

nisadministeredintravenously,itsbioavailabilityis100%.[1]However,whenamedicationisadministeredviaotherroutes(suchasorally),itsbio

availabilitydecreases(duetoincompleteabsorptionandfirst-passmetabolism)ormayvaryfrompatienttopatient(duetointer-indiv

idualvariation).•Absolutebioavailability(绝对生物利用度）isthefractionofthedrugabsorbedthroughnon-intravenousadministrationcomparedwiththecorrespondingint

ravenousadministrationofthesamedrugAbsolutebioavailability（绝对F）：F＝AUCpoAUCIV×100%（相对生物利用度）（相对）：F＝AUCtestedAUCstandard×1

00%AUC(iv)AUC(po)PlotofCpversusTimeafterIVandIMAdministration.NOTE:AUCsarealmostsame.•FoodEffectsonBioa

vailability•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。•Mayaffectrateandextentin

dependently.•FoodEffectsGImotilityandalsocanincreasesolubilizationofdrugs•Changemaydependoncontentofmeal•Foodmaymitigate（decrease)nausea•Vomit

ingtendstodecreasebioavailability•Timeofdosewithrespecttofood。（根据不同食物，选择不同服药时间）。Bioequivalence(生物等效性)meansthatonebra

ndordosageformofadrugorsupplementisequivalenttoareferencebrandordosageformofthesamedrugintermsofbioavailabilityparametersmeasuredviain

vivotestinginhumansubjects.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。•AUC–Areaundertheconcentration-timecurve•Cmax–Maximumconcentration–Adifferenceofgreaterthan20%inCmaxortheAUCrepresents

asignificantdifferencebetweenthestudyandreferencecompounds•Tmax–TimetomaximumconcentrationStudyCompoundReferenceCompoundTimeConcentrationCm

axTmaxAUC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80～120%范围内，称为“等效性检验”。其中AUC等效反映了吸收数量相近，Tm

ax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）•Distributionistheprocessbywhichadrugdiffusesori

stransferredfromintravascularspacetoextra-vascularspace(bodytissues).Inthesimplestofterms,adrug‘svolumeofdistributionisthatvolumeofbodilyfl

uidintowhichadrugdoseisdissolved.Therefore,ifweknowthedosethatwasgiven,andwecanmeasuretheserumlevel(concentration),thenwecan

calculateavolume:(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)istheamountofdruginthebodydividedbytheconcentrationi

ntheblood.Drugsthatarehighlylipidsoluble,suchasdigoxin,haveaveryhighvolumeofdistribution(500litres).Drugswhicharelipidinsoluble,suchasneurom

uscularblockers,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(concentr

ation)•Systemicdistribution–Plasma3L（血浆）–Extra-cellular15L（细胞外液）–Intra-cellular40L（细胞内液）•Bindingtobloodp

roteins•Unevendistributioninbodyorgans–Depositioninfattissue–Depositioninliver/kidneys–Depositionintargetorgan•Internalbarriers-Bl

oodbrainbarrier/PlacentaQ-Describefactorsinfluencingdrugdistribution1.bodyfactor(1)组织屏障Tissuebarrier(a)血脑屏障Bloodbrainbarrier,胎盘屏障plac

entabarrier,gastrointestinalmucosa,epithelialbarrierofskinorbladder.(Thebarriersbetweenbraincellandbl

ood,braincellandcerebrospinalfluid,aswellasbloodandcerebrospinalfluidarecalledbloodbrainbarrier.Nowhereinthebodyistheremoreneedforho

meostasisthaninthebrain.Bloodbrainbarrierprotectsbrainfromcirculatingtoxin,highMWorhighlywatersolubledrugs,e.g.,quaternaryamines,andharmfu

lsolutes.Ifneeded,lipidsolubleagentisavailable.)Over100yearsago,theconceptofthebloodbrainbarrierwasfirstintroducedbyP

aulEhrlich.Hefoundthatintravenousinjectionofdyesintothebloodstreamstainedallthetissuesinmostorgansexceptbrainandspinalcord。Theresultssugges

tthattheremustbeabarrierbetweenbrainandbody(b)Placentabarrier（胎盘屏障）Mostdrugscancrosstheplacentaandenterth

ebreastmilk.Thedifferenceisthelimitedmaternalbloodflowingintoplacenta,thefastesttimefordrugequilibrationbetweenmotherandfetusisinth

eorderof10-15min.•Drugsharmfultofetusshouldnotbegiventopregnantwoman.孕妇应避免服用对胎儿有害的药物(2)Absorbingsurface(3)Bloodflow(4)EnvironmentalpH(5)Diseas

estates•Drugcanbedividedintoweakacidandweakbase(弱酸性药物与弱碱性药物)•Q-Describetheformofweakacidinacidicandbasicsolution.•Q-Describetheformofweakbaseinacid

icandbasicsolution.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WeakAcid

sRelease/DonateH+HAH++A-WeakBasesBind/AcceptH+H++BHB+HAH+↑+A-H+↑+BHB+Ionizedform(charged)A-Un-ionizedform(

uncharged)HAHALipidBilayer弱酸与弱碱在细胞膜内外分布IonizedformA-Non-IonizedformHABHB+IntracellularpHi=7.0Plasma,ExtracellularpHe=7.4Non-I

onizedformIonizedform•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.•Mostdr

ugsareweakelectrolytes,andpresenceinbothunionizedandionizedforms.Theunionizedformhasstrongerlipid-so

lubilityandiseasiertodiffuseacrossthemembraneduetothelipoidcharacteristicsofthebiologicalmembrane.Theion

izedformwhichhasstrongerpolarityisdifficulttodiffuseacrossthemembraneduetothewatersolubilityandiseasiertobeexcretedfromkidney.Lipi

dBilayerSmall,unchargedLarge,unchargedSmallchargedionsH2O,urea,CO2,O2,N2GlucoseSucroseH+,Na+,K+,Ca2+,Cl-,HCO3-DENIED!DENIED!Sw

oosh!HydrophobicTailsHydrophilicHeads跨膜转运WeakacidpH–pKa=lg(A-/HA)AcidicdrugsarebestabsorbedfromacidicenvironmentsWeakbasepKa-pH=lg(BH+/B)

BasicdrugsarebestabsorbedfrombasicenvironmentsnumeratorDenominator弱酸弱碱解离度与环境pH的关系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•pH–pKa=lg(A-/HA)=9－7=2=lg(100/1)易排泄/难吸收。•pH=5的情况pH–pKa=lg(A-/HA)=5－7=-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/excretion•pH=9,及pH=5（1）pH=9的情况•pKa–pH

=lg(BH+/B)=7－9=-2=lg(1/100)难排泄/易吸收。（2）pH=5的情况pKa–pH=lg(BH+/B)=7－5=2=lg(100/1)易排泄/难吸收。•Q-HowtocalculatethepKaofadrug•pKaisthepHatwhicht

heconcentrationofionizedandun-ionizeddrugissame(50%each)forbothweakacidicandbasicdrugs•Forbothweakacidicandbasicdrugs,e.g.,their

pKamaybe3.1,4.6,5.3,7.4,8.6,9.2etc,atwhichthedrugconcentrationofionizedandun-ionizedformissame.Pleasedes

cribetheimportanceofdrugPlasmaProteinbinding(DPPB)（药物-血浆蛋白结合的重要性）1.Onlyfreedrughaspharmacologicaleffects,2.Reductionofdrugdistributio

n,biotrans-formationandexcretion3.Drug-plasmaproteinbindingisreversibleandisservedasadrugreservoir4.Acompetitionsiteformanydifferentdrugs5.DPPBac

tasatransportmechanismforthedrugtothesiteofactionorelimination.(relatedtodrugdistribution)WhereisDrugstoredinthebody•(1)Plasmar

eservoir•(2)Cellular(tissue)Reservoir•(3)FatReservoir•(4)BoneReservoirBIOTRANSFORMATION1•Definition•Biotra

nsformationisanenzyme-mediatedtransformationofonechemicalintoanotherwithinthelivingorganism,e.g.,chemicaltransformationsofforeigncompoundsinc

ludingdrugs.（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)•Si

gnificance•Evolutionhasprovideduswithmechanismstoeliminatetheseforeigncompoundsfromourinternalenvironment.•Manydrugsarehighlylipid-soluble,

unionizedatnormalpH,areeithernotreadilyfilteredattheglomerulusorareeffectivelyre-absorpedinthekidney.theyarebio-transformedi

ntoaninactive,morecharged,water-solublemetabolitetoexcrete.BIOTRANSFORMATION2•Consequenceofbiotransformation（生物转

化的结果）(1)Inactivationandmorewatersoluble(most),e.g.,acetylsalicylicacid(aspirin)→aceticacid+salicylate.(2)Activecompound→activecompound,e.g.,diaze

pam（地西泮）→oxazepam（奥沙西泮）.(3)Activation,e.g.,L-dopa（左旋多巴）→dopamine.（多巴胺）•Thedifferencebetweenbiotransformationandmetabolism•metabolismmeans"breakdo

wn"and"inactivation".However,biotransformationincludenotonly"breakdown"and"inactivation”butalsosyntheticreactions.BiotransformationReactions

(BR)•BRincludephaseIandphaseIIreactions.•FeaturesofphaseIreactions（I相反应的特征）A.Converttheparentcompoundtoamorepolarmetabolit

ebyintroducingorbyunmaskingafunctionalgroupsuchasan-OH,-SH,orNH2group.PhaseIreactionsincludeoxidation,reductionandhydrolysis.B.Themetab

olitesresultingfromaphaseIreactioncanbeinactive,lessactive,oroccasionallymoreactivethantheparentcompound.C.PhaseIReactionsdonotrequiree

nergy.•PHASEIREACTIONSPHASEIREACTIONSReactionsClassStructuralChangeDrugSubstratesOxidationsP450-Aromatichydroxylations•Propranol

ol,phenobarbital,phenytoin,amphetamine,warfarin-Aliphatichydroxylations•Amobarbital,pentobarbital,chlorpropamide,ib

uprofen,digitoxinRCH2CH3RCH2CH2OHRCH2CH3RCHCH3OHPHASEIREACTIONSReactionsClassStructuralChangeDrugSubstrate

s-Oxidativedealkylation-O-dealkylation-S-dealkylation•Codeine,p-nitroanisole•6-methylthiopurine•Aniline,chlorphentermine•2-acetylamino-fluorene,a

cetaminophenROCH3ROH+CH2ORSCH3RSH+CH2ON-oxidation1°amines2°aminesRNH2RNHOHR1NHR2R1NOHR2CH3OCHOHNCH3OCHONSO3-

C6H8O6-NOHCOCH3NOHCOCH3SGNOHCOCH3Acetaminophen(APAP)PAPSPAPPhenolsulfo-transferaseAPAPSulfateUDP-glucuronosyl-transferaseUDPUDPGAAPAPGl

ucuronideGSHGlutathioneconjugateN-acetyl-p-benzoquinoneimine(toxic)P450,PHS◼PhaseII(SyntheticorConjug

ation结合)ReactionsA.usuallyrequireenergy,nearlyalwaysinactivatesparentcompound,withfewexception.B.PhaseIIreactionsar

e"conjugationreactions".Inhumans,glucuronidationisthemostimportantone.C.Theconjugationreactionsfrequentlyoc

curafteraninitialPhaseIreaction.Thereactionistomakethedrugmorepolar,andmorereadilyexcreted.PhaseIandIIreactionsCytochromeP450enzymes细胞色素P45

0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）increaseacti

vitiesofHDME)•Subtype:18differentformsofcytochromeP450(CYP)identifiedinhumans;eachtheproductofaseparat

egene.ImportantcytochromeP450sinhumansare:CYP3A,CYP1A2,CYP2C,CYP2D6,CYP2E1.•CYPfamilyofenzymesimportanttodrugdegradationinliverandinsm

allintestine.Whydrugmetabolizingenzymeisimportantfordrugtherapy?Sixtypercentoforaldrugsmetabolizedprimarilybyaspecific

formofHDME-CYP3AFortypercentofdrugcandidatesfailbecauseoforalbioavailabilityproblemsOvercomingthe‘firstpasseffect’mayresultinhighoraldosesorresort

ingtoIVadministrationCYP3Ainhibitorsboostoralbioavailability•Geneticdifference(mostimportant):geneticdifferencesinpeople’sabilitiestometabolizedr

ugsthroughcertainmetabolicpathways•Environmentalfactors:Exposuretoenvironmentalpollutants&industrialchemicals•Physiologicalf

actors:Disease,gender,age(drugmetabolisminelderly)•hepaticdrugmetabolizingenzyme:Induction/inhibition•Metabolicdruginteractio

n•QDothesefactorsaffectpharmacologicaleffectsofadrug?影响药物生物转化的因素一室模型与二室模型OnecompartmentTwocompartmentevenly(harmonio

usly)distributed•Q-Describethecharacterizationoffirstorderkinetics（一级动力学）•Aconstantfractionofthedruginthebodyiseliminatedperunitti

me.Therateofeliminationisproportionaltotheamountofdruginthebody.Themajorityofdrugsareeliminatedinthisway.•dC/dt＝-KeC(Ke:Eli

minationrateconstant，消除速率常数)•C=C0e-kt(Ke＝Km（代谢速率常数）＋Kex（排泄速率常数）。••Concentration(C)intheplasmadecreasesatarateproportionalatallt

imes(t)tothedrugconcentrationitself.（代谢速率与血药浓度成正比）•Thehalflifeoffirstorderkineticsisconstant.（半衰期恒定）•Mostdrugsdisposedinthemanneroffirstorderk

ineticsinasemilogarithmicfashion(timevslnCislinear).（时间与血药浓度对数作图为一直线）。ZeroOrderKinetics零级动力学•-dC/dt=K•Therateofdrugeliminationisconsta

nt.（消除速率恒定，因为达到了肝药酶的最大代谢能力）。•Thepseudohalf-lifeisproportionaltothedose.（半衰期与剂量成正比）•Graphically,thedrugconcentration

vstimeyieldsastraightline.（浓度对时间作图为一直线）。•TheeliminationofmostdrugsundergoesFirstorderkinetics.However,ifinhighdoses,theeliminationofsomedr

ugschangedintoZeroorderkinetics,becauseofthesaturationofhepaticdrug-metabolizingenzyme,e.g.,aspirin.（肝药酶的饱和）lgC

CttFirstorderkineticsZeroorderkineticsHalf-life(t1/2)(first-orderkinetics)半衰期•dC/dt＝-KeC,dC/C＝-Kedt•Ct/C0＝e-Ket•ln(Ct/C0)＝-K

etWhenCt＝½C0•ln((1/2)Ct/C0)＝ln(1/2)＝-ln2•-ln2＝-Ket1/2•ln2/Ke＝t1/2t1/2＝0.693/Ke•Half-life(t1/2)Eliminationhalflife:thetimetakenfordrugp

lasmaconcentrationtoreduceby50%.After4halflives,eliminationis94%complete.半衰期：药物在血浆中消除一半所需要的时间K=0.693/t1/2Onet1/2（8h

）onedose，4-6t1/2reachtoCss(steadystateconcentration)（50%，75%，87.5%,93.8%,96.9%,98.5%)最小有效血药浓度•思维综合锻炼（摘

自美国医师考试，略加修改）•Apatientof70kgwasgivenadrug(5mg/kg)intravenously.Thedrugplasmaconcentrationsweremeasur

edaftertheendoftheadministration.•Seegraphnextpage.201075321018mg/Lαphase—distributionphaseβphase—eliminationphaseTimeafterdosin

gstoppedDrugplasmaC(h)mg/L0.018.00.510.01.05.82.04.63.03.74.03.05.02.46.01.98.01.3Q.Theeliminationhalf-

life(t1/2)ofthedruginthepatientisapproximately•A.0.5h•B.1.0h•C.2.0h•D.3.0h*•E.4.0h•Theeliminationconstant(ke)ofthedruginthepatientwasapproximately•A

.0.17h-1•B.0.23h-1*•C.0.35h-1•D.0.69h-1•E.1.39h-1•t1/2(h)=0.693/ke;ke=0.693/t1/2(h)•QVd(Theapparentvolumeofdistribution)inthepatientwasapproximately

•A.10L•B.20L•C.30L•D.40L•E.50L•••Vd=A/C=totalamountofdruginthebodyDCinplasmaat0timeofelimination5mgx70kg=350mg7mg/L=7mg/L=50LDC=DrugConcentratio

n•ExcretionofDrugs药物排泄•Drugseliminatedasmetabolites(common),asunchangeddrug(rare)主要以代谢产物形式排泄•（Polarmetabolitesmoreeasil

yexcretedthanlipidsolublecompounds）水溶性代谢产物易排泄•Kidney:mostimportantorganofexcretion(urine)排泄器官肾脏••Otherexcretoryorgansincludeintestin

es•(bile&faeces),lungs(exhaledair),breastmilkandsweatRenalExcretion-2•Renalexcretioninvolves:•Glomerularfiltration（肾小球滤过）dependi

ngonGlomeruarfiltrationrate&plasmaproteinbinding•Activetubularsecretion(主动肾小管分泌）:organicanions&cationsaddedtoglomerularfiltratebyactive

carrier-mediatedsecretioninproximaltubule(e.g.penicillin)•Tubularreabsorption:nonionisedformsofweakacids&basesundergoreabsorption,by

passivediffusion(pHdependent)•Renaldisease–Slowsexcretion–Prolongseffects•Renalclearanceisdefinedasthevolu

meofplasmathatistotallyclearedofadrugin1minduringpassagethroughthekidneys.•Hepaticclearanceisdefinedasthevolumeofplasm

athatistotallyclearedofdrugin1minduringpassagethroughtheliver.总清除率（totalbodyclearanceorplasmaclearance）指机体内各消除器官在

单位时间内清除药物的血浆容积，是肝肾等）CL=Vd·Ke(Vd=表观分布常数，Ke=消除常数=0.693/t1/2)Apatienthasoverdosedonphenobartital.Phenobarbit

alisanacid.Ifwe‘alkalinalize’theurinebygivingbicarbonatewhatwillhappentothephenobarbitalmoleculesastheyarefilteredthroughtherenaltubules?UrinepHandEl

imination：ivNaHCO3+phenobarbitalpH≥8.0O：ivNa2SO4+phenobarbital；pH≤7.0RelationshipBetweenAbsorption,Distribution,andEliminat

ionAbsorptionDistributionEliminationRelationshipBetweenAbsorption,Distribution,andElimination（2）Pharmacokinetics＆pharmacodynamicsvstimePea

kofPharmacologicaleffects,adverseeffects(Peakconcentration)