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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-Descr

ibewhatispharmacokinetics?•Thestudyofthedynamicchangesofdrugsinthebody,thatis,theprocessofabsorption,distributio

n,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,distrib

ution,biotransformationandexcretion.•Whathappenstodrug:looseactivity,increaseionicsolubility.•Whatfactors

influencethejourneyofadruginthebody?•药动学在科研方面的应用:Quantitativedescriptionofthetimecourseofdrugandmetaboliteconcentrationsinplasma,tissueandurin

e.•药动学的临床应用:GuidefordrugchoiceandadjustmentofdosageDistribution(tissue)DrugPlasmaBio-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,drugscrossvar

iousbiologicalmembranes,by被动转运passivetransportor/and主动转运（activetransport）.•Drugtrans-membranetransportar

einvolvedinAbsorption,distribution,andExcretion.•CanyoudescribethatwhatdependsonforaAdrugtocrosscellmembrane

s?•Aretheresomethingsharedincommon?UnderstandFactorsinfluencestheprocess.1.molecularsize&shape2.solubilityatsightofabsorption3.ionisati

on4.lipidsolubilityFeatureandimportanceofPassivetransport（被动转运）(a)Themajorityofdrugsaretransportedbypassi

vetransport：Simplediffusion,Filtration，andsomebyFacilitateddiffusion(transport).Commonfeatures:(a)transportfromhightolowconcentration,anddependsoncon

centrationgradient;(b)needsnoenergy;(c)influencedbylipidsolubilityofdrugandbydifferencesinpHacrossthemembrane.Difference

:Facilitateddiffusion(a)needscarrier;(b)hasdrugtransportsaturation;(c)hasdrugcompetitionandselectivity.Simplediffusion,Fil

trationNocarrierneeded.2.Activetransport（主动转运）Activetransporthasfollowingfeatures:(a)needsspecialcarriers;(b)Requireme

ntofenergyconsumption.(c)Drugscantransportfromlowtohighconcentration.(d)presencetransportsaturationand(e)presenceofcompetitiveinhibiti

on.AlternativeclassificationCarriermediatedtransport（载体转运）:ActivetransportandFacilitatedtransport（主动转运与易化转运）Non-carriermediatedtransport:Simple

diffusion,andFiltration（非载体转运）•carrier-mediatedtransport:Movementwhichoccursacrossmembranes,suchastheblood–brainbarrierandtheg

astrointestinalmucosa.Themechanismisalsocharacterizedby(1)beingsaturable;(2)competitiveinhibitionoccurs

.Therearetwoformsofcarrier-mediatedtransport,activetransportandfacilitateddiffusion.Therapidtransferofdrugmetabolitesintourineisbyactivetransport.

Entryofglucoseintomostcellsisbyfacilitateddiffusionbutitspassageacrossthegastrointestinalmucosaisbyactivetranspor

t.Passiveandactivetransport-2II.Theprocessofdrugtransport•Q-Whatisdrugabsorption（吸收）?Doallkindsofadministra

tionpossessabsorption?MovementofdrugmoleculesfromthesiteofadministrationtothesystemiccirculationbypassingthecellmembranebarrieriscalledAbsorpt

ion.•DrugadministrationOraladministration,(mostpopular,advantage:convenient,economical,andofefficiencyforabsorption).Di

sadvantage:irritationtogastrointestinalmucosa,irregularityinabsorption,andFirstpasseffect（metabolism,首关效应）,whichmeans

thatorallyadministereddrugsaremetabolizedinintestinalflora,andliverwhenabsorbedfromhepaticportalsystembeforetheyfirstgai

naccesstothegeneralcirculation.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•（Hepatoenteralcircul

ation,肝肠循环）:Drugisexcretedintothesmall,intestinebybilesecretion,andabsorbedthereagainiscalledhepatoenteralcirculation.PlotofCpversusTimeforAa

ndB;BhavingSlowerAbsorptionDoabsorptioninvolveinanytypeofadministration?TheimportanceofHepatic‘First-Pa

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

dintoportalcirculation,mustpassthroughlivertoreachsystemiccirculation•Mayreducebioavailability（生物利用度）ofdrug。•Firstpasseffectisalso

atypeofbiotransformation,i.e.,theeliminationofasubstance,e.g.,adrugintheliverafterabsorptionfromtheintestineandbeforei

treachesthesystemiccirculation.•Sublingual（舌下）Drugsabsorbedsublinguallymeansdrugsareabsorbedthroughmouththinmucosaanddonothavefirstp

asseffectingastro-intestine.硝酸甘油（Nitroglycerin）•InjectionIntravenous(i.v.):directtogeneralcirculationandismostfastway.Theotherinjection

include:subcutaneous,intra-muscular.•Rectalmucosa（直肠粘膜）Advantage:Avoidvomiting,nofirstpasseffect,usedwhenpa

tientisun-coconscious.Disadvantage:rectalabsorptionisoftenirregularandincomplete.•IV(静脉注射injectionandinfusion)doesnotneedabsorption.•Local

anesthesia: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%DosereachesthesystemiccirculationDose(administered)=ivadministrationF＝×100%定义与公式见的关系，是否可用公式代替定义？•Bioava

ilabilityisusedtodescribethefractionofanadministereddoseofunchangeddrugthatreachesthesystemiccirculation,oneoftheprincipalpharmac

okineticpropertiesofdrugs.Bydefinition,whenamedicationisadministeredintravenously,itsbioavailabilityis100%.[

1]However,whenamedicationisadministeredviaotherroutes(suchasorally),itsbioavailabilitydecreases(duetoincompleteabsorptionandfirst-passmetabolism)o

rmayvaryfrompatienttopatient(duetointer-individualvariation).•Absolutebioavailability(绝对生物利用度）isthefractionofthedrugabsorbedthrough

non-intravenousadministrationcomparedwiththecorrespondingintravenousadministrationofthesamedrugAbsolutebioava

ilability（绝对F）：F＝AUCpoAUCIV×100%（相对生物利用度）（相对）：F＝AUCtestedAUCstandard×100%AUC(iv)AUC(po)PlotofCpversusTimeafterIVandIMAdministration.N

OTE: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/ortheextentofab

sorption。•Mayaffectrateandextentindependently.•FoodEffectsGImotilityandalsocanincreasesolubilizationofdrugs•Changemaydependoncontentofmeal•Foodmay

mitigate（decrease)nausea•Vomitingtendstodecreasebioavailability•Timeofdosewithrespecttofood。（根据不同食物，选择不

同服药时间）。Bioequivalence(生物等效性)meansthatonebrandordosageformofadrugorsupplementisequivalenttoareferencebrandordosageformofthesamedrugintermsofbioa

vailabilityparametersmeasuredviainvivotestinginhumansubjects.Bio-equivalenceofhumandrugsmustbedeterminedinhumansviaestablishedmeasuresofbioava

ilability.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–Ad

ifferenceofgreaterthan20%inCmaxortheAUCrepresentsasignificantdifferencebetweenthestudyandreferencecompounds•Tmax–Time

tomaximumconcentrationStudyCompoundReferenceCompoundTimeConcentrationCmaxTmaxAUC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，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-Whatisdrugdistri

bution（分布）•Distributionistheprocessbywhichadrugdiffusesoristransferredfromintravascularspacetoextra-vasculars

pace(bodytissues).Inthesimplestofterms,adrug‘svolumeofdistributionisthatvolumeofbodilyfluidintowhichadrugdoseisdissolved.Therefore,ifweknowthed

osethatwasgiven,andwecanmeasuretheserumlevel(concentration),thenwecancalculateavolume:(药物自血液系统进入组织的过程)•Volumeofdistribution=Dose/drugc

oncentration;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,haveaveryhighvolumeof

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

液）•Bindingtobloodproteins•Unevendistributioninbodyorgans–Depositioninfattissue–Depositioninliver/kidneys–D

epositionintargetorgan•Internalbarriers-Bloodbrainbarrier/PlacentaQ-Describefactorsinfluencingdrugdistribution

1.bodyfactor(1)组织屏障Tissuebarrier(a)血脑屏障Bloodbrainbarrier,胎盘屏障placentabarrier,gastrointestinalmucosa,epithelialbarrierofskinor

bladder.(Thebarriersbetweenbraincellandblood,braincellandcerebrospinalfluid,aswellasbloodandcerebrospinalfluidarecalledbloodbrain

barrier.Nowhereinthebodyistheremoreneedforhomeostasisthaninthebrain.Bloodbrainbarrierprotectsbrainfrom

circulatingtoxin,highMWorhighlywatersolubledrugs,e.g.,quaternaryamines,andharmfulsolutes.Ifneeded,lipidsolubleagentisavailable.)Over100years

ago,theconceptofthebloodbrainbarrierwasfirstintroducedbyPaulEhrlich.Hefoundthatintravenousinjectionofdyesintothebloodstreamstainedallthetissue

sinmostorgansexceptbrainandspinalcord。Theresultssuggestthattheremustbeabarrierbetweenbrainandbody(b)Placentabarrier（胎盘屏障）Mostdrugsc

ancrosstheplacentaandenterthebreastmilk.Thedifferenceisthelimitedmaternalbloodflowingintoplacenta,thefastesttimefordrugequilibrati

onbetweenmotherandfetusisintheorderof10-15min.•Drugsharmfultofetusshouldnotbegiventopregnantwoman.孕妇应避免服用对胎儿有害的药

物(2)Absorbingsurface(3)Bloodflow(4)EnvironmentalpH(5)Diseasestates•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WeakAcidsRelease/DonateH+HAH++A-WeakBasesB

ind/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Ionizedform

A-Non-IonizedformHABHB+IntracellularpHi=7.0Plasma,ExtracellularpHe=7.4Non-IonizedformIonizedform•Describewhydruglipid/watersolubilityinfluencedrug

absorption/distribution/excretion?•（为什么药物的脂/水溶性影响药物的吸收/分布/排泄）•Drugdiffusionacrossmembraneisaffectedbythephysicochemicalproperti

esofdrugssuchasmolecularweight,polarity,lipid/watersolubility.•Mostdrugsareweakelectrolytes,andpresenceinbothunion

izedandionizedforms.Theunionizedformhasstrongerlipid-solubilityandiseasiertodiffuseacrossthemembraneduetothelipoidcharacteristicsof

thebiologicalmembrane.Theionizedformwhichhasstrongerpolarityisdifficulttodiffuseacrossthemembraneduetothewatersolubilitya

ndiseasiertobeexcretedfromkidney.LipidBilayerSmall,unchargedLarge,unchargedSmallchargedionsH2O,urea,CO2,O2,N2G

lucoseSucroseH+,Na+,K+,Ca2+,Cl-,HCO3-DENIED!DENIED!Swoosh!HydrophobicTailsHydrophilicHeads跨膜转运WeakacidpH–pKa=l

g(A-/HA)AcidicdrugsarebestabsorbedfromacidicenvironmentsWeakbasepKa-pH=lg(BH+/B)Basicdrugsarebestabsorbedfrombasicenvironmentsnu

meratorDenominator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=l

g(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•pKaisthepHatwhichtheconcentratio

nofionizedandun-ionizeddrugissame(50%each)forbothweakacidicandbasicdrugs•Forbothweakacidicandbasicdrugs,e.g.,theirpKamaybe3.1,4.6,5.3

,7.4,8.6,9.2etc,atwhichthedrugconcentrationofionizedandun-ionizedformissame.PleasedescribetheimportanceofdrugP

lasmaProteinbinding(DPPB)（药物-血浆蛋白结合的重要性）1.Onlyfreedrughaspharmacologicaleffects,2.Reductionofdrugdistribution,biotrans-formationandexcretion3.Dru

g-plasmaproteinbindingisreversibleandisservedasadrugreservoir4.Acompetitionsiteformanydifferentdrugs5.DPPBactasatransport

mechanismforthedrugtothesiteofactionorelimination.(relatedtodrugdistribution)WhereisDrugstoredinthebody•(1)Plasm

areservoir•(2)Cellular(tissue)Reservoir•(3)FatReservoir•(4)BoneReservoirBIOTRANSFORMATION1•Definition•Biotransf

ormationisanenzyme-mediatedtransformationofonechemicalintoanotherwithinthelivingorganism,e.g.,chemicaltransfo

rmationsofforeigncompoundsincludingdrugs.（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,andki

dney,etc.(主要转化部位：肝脏)•Significance•Evolutionhasprovideduswithmechanismstoeliminatetheseforeigncompoundsfromourinternalenvironment.•Manydrugsar

ehighlylipid-soluble,unionizedatnormalpH,areeithernotreadilyfilteredattheglomerulusorareeffectivelyre-absorpe

dinthekidney.theyarebio-transformedintoaninactive,morecharged,water-solublemetabolitetoexcrete.BIOTRANSFORMATION2•Consequenceofbiotransfor

mation（生物转化的结果）(1)Inactivationandmorewatersoluble(most),e.g.,acetylsalicylicacid(aspirin)→aceticacid+salicylate.(2)Activecom

pound→activecompound,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）•Thedifferencebetweenbio

transformationandmetabolism•metabolismmeans"breakdown"and"inactivation".However,biotransformationincludenotonly"breakdown"and"inactivatio

n”butalsosyntheticreactions.BiotransformationReactions(BR)•BRincludephaseIandphaseIIreactions.•FeaturesofphaseIreaction

s（I相反应的特征）A.Converttheparentcompoundtoamorepolarmetabolitebyintroducingorbyunmaskingafunctionalgroupsuchasan-OH,-SH,orN

H2group.PhaseIreactionsincludeoxidation,reductionandhydrolysis.B.ThemetabolitesresultingfromaphaseIreactioncanbeinactive,lessactive,or

occasionallymoreactivethantheparentcompound.C.PhaseIReactionsdonotrequireenergy.•PHASEIREACTIONSPHASEIREACTI

ONSReactionsClassStructuralChangeDrugSubstratesOxidationsP450-Aromatichydroxylations•Propranolol,phenoba

rbital,phenytoin,amphetamine,warfarin-Aliphatichydroxylations•Amobarbital,pentobarbital,chlorpropamide,ibuprofen,digitoxinRCH2CH3RCH

2CH2OHRCH2CH3RCHCH3OHPHASEIREACTIONSReactionsClassStructuralChangeDrugSubstrates-Oxidativedealkylation-O-dealkylation-S-dealkylation•Codeine,p-nitro

anisole•6-methylthiopurine•Aniline,chlorphentermine•2-acetylamino-fluorene,acetaminophenROCH3ROH+CH2ORSCH3RSH+CH2ON-oxidation1°amines2°aminesRN

H2RNHOHR1NHR2R1NOHR2CH3OCHOHNCH3OCHONSO3-C6H8O6-NOHCOCH3NOHCOCH3SGNOHCOCH3Acetaminophen(APAP)PAPSPAPPhenolsulfo-t

ransferaseAPAPSulfateUDP-glucuronosyl-transferaseUDPUDPGAAPAPGlucuronideGSHGlutathioneconjugateN-acetyl-p-benzoquinoneimine(toxic)P45

0,PHS◼PhaseII(SyntheticorConjugation结合)ReactionsA.usuallyrequireenergy,nearlyalwaysinactivatesparentcompound,withfewexception.B.PhaseIIr

eactionsare"conjugationreactions".Inhumans,glucuronidationisthemostimportantone.C.Theconjugationreactionsfrequentlyoccurafterani

nitialPhaseIreaction.Thereactionistomakethedrugmorepolar,andmorereadilyexcreted.PhaseIandIIreactionsCytochromeP450enzymes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,and

thekeystepistoinsertanO2intothesubstrate.•CharacteristicsofHDME（肝药酶作用的特征）•Non-selective:（非选择性）Alldrug

s(foreignsubstance)canbebiotransformed(detoxification).•Inducible(可诱导）increaseactivitiesofHDME)•Subtype:18differentformsofcytochromeP450(CYP)iden

tifiedinhumans;eachtheproductofaseparategene.ImportantcytochromeP450sinhumansare:CYP3A,CYP1A2,CYP2C,CYP2D6,CYP2E1.•CYPfamilyofenzymesimportanttod

rugdegradationinliverandinsmallintestine.Whydrugmetabolizingenzymeisimportantfordrugtherapy?Sixtypercentoforaldrugsmetabolizedprimarilybyaspeci

ficformofHDME-CYP3AFortypercentofdrugcandidatesfailbecauseoforalbioavailabilityproblemsOvercomingthe

‘firstpasseffect’mayresultinhighoraldosesorresortingtoIVadministrationCYP3Ainhibitorsboostoralbioavailability•Geneticdifference

(mostimportant):geneticdifferencesinpeople’sabilitiestometabolizedrugsthroughcertainmetabolicpathways•Environmentalfac

tors:Exposuretoenvironmentalpollutants&industrialchemicals•Physiologicalfactors:Disease,gender,age(drugmetabolisminelderly)•

hepaticdrugmetabolizingenzyme:Induction/inhibition•Metabolicdruginteraction•QDothesefactorsaffectpharmacologicaleffectsofadrug?影响药物生物转化的因素一室模型与二室模

型OnecompartmentTwocompartmentevenly(harmoniously)distributed•Q-Describethecharacterizationoffirstorderkinetics（一级动力学）•Aconstantfractionofthedruginth

ebodyiseliminatedperunittime.Therateofeliminationisproportionaltotheamountofdruginthebody.Themajorityo

fdrugsareeliminatedinthisway.•dC/dt＝-KeC(Ke:Eliminationrateconstant，消除速率常数)•C=C0e-kt(Ke＝Km（代谢速率常数）＋Kex（排泄速率常数）。••Concentrati

on(C)intheplasmadecreasesatarateproportionalatalltimes(t)tothedrugconcentrationitself.（代谢速率与血药浓度成正比）•Thehalflifeoffirstorderkine

ticsisconstant.（半衰期恒定）•Mostdrugsdisposedinthemanneroffirstorderkineticsinasemilogarithmicfashion(timevslnCislinear).（时间与血药浓度对数作图为一直线）。ZeroOr

derKinetics零级动力学•-dC/dt=K•Therateofdrugeliminationisconstant.（消除速率恒定，因为达到了肝药酶的最大代谢能力）。•Thepseudohalf-lifeispropor

tionaltothedose.（半衰期与剂量成正比）•Graphically,thedrugconcentrationvstimeyieldsastraightline.（浓度对时间作图为一直线）。•The

eliminationofmostdrugsundergoesFirstorderkinetics.However,ifinhighdoses,theeliminationofsomedrugschangedintoZeroorderkinetics,becauseofthes

aturationofhepaticdrug-metabolizingenzyme,e.g.,aspirin.（肝药酶的饱和）lgCCttFirstorderkineticsZeroorderkineticsHalf-life(t1/2)(first-o

rderkinetics)半衰期•dC/dt＝-KeC,dC/C＝-Kedt•Ct/C0＝e-Ket•ln(Ct/C0)＝-KetWhenCt＝½C0•ln((1/2)Ct/C0)＝ln(1/2)＝-l

n2•-ln2＝-Ket1/2•ln2/Ke＝t1/2t1/2＝0.693/Ke•Half-life(t1/2)Eliminationhalflife:thetimetakenfordrugplasmaconcentrationtoreduceby50

%.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(steadystateconcentrat

ion)（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.Thedrugplasmaconcentrationswer

emeasuredaftertheendoftheadministration.•Seegraphnextpage.201075321018mg/Lαphase—distributionphaseβphase—eliminationphaseTimeafterdosingstoppedDrugp

lasmaC(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=DrugConcentration•E

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

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

therexcretoryorgansincludeintestines•(bile&faeces),lungs(exhaledair),breastmilkandsweatRenalExcretion-2•Renalexcretioninv

olves:•Glomerularfiltration（肾小球滤过）dependingonGlomeruarfiltrationrate&plasmaproteinbinding•Activetubularsecret

ion(主动肾小管分泌）:organicanions&cationsaddedtoglomerularfiltratebyactivecarrier-mediatedsecretioninproximaltubule(e.g.penicilli

n)•Tubularreabsorption:nonionisedformsofweakacids&basesundergoreabsorption,bypassivediffusion(pHdependent)•Renaldisease–Slowsexcretion–Prolongs

effects•Renalclearanceisdefinedasthevolumeofplasmathatistotallyclearedofadrugin1minduringpassagethroughthekidneys.•Hepaticclearanceisdefinedasthevol

umeofplasmathatistotallyclearedofdrugin1minduringpassagethroughtheliver.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.Phenobarbitalisanacid.Ifwe‘alkalinalize’theur

inebygivingbicarbonatewhatwillhappentothephenobarbitalmoleculesastheyarefilteredthroughtherenaltubules?UrinepHandElimination：iv

NaHCO3+phenobarbitalpH≥8.0O：ivNa2SO4+phenobarbital；pH≤7.0RelationshipBetweenAbsorption,Distribution,andEliminationAbsorptionDistributionElimin

ationRelationshipBetweenAbsorption,Distribution,andElimination（2）Pharmacokinetics＆pharmacodynamicsvstimePeakofPharmacologicaleffects,adverseeffec

ts(Peakconcentration)