pharmacokinetics.pptx

Chapter2Pharmacokinetics,DepartmentofpharmacologyM.Y.Liu,Pharmacokinetics,TransmembranetransportProcessesofdruginthebodyBasicconceptsofpharmacokinetics,Part1Transmembranetransportofdrugs,Bound,Free,Free,Bound,LOCUSOFACTION“RECEPTORS”,TISSUERESERVOIRS,SYSTEMICCIRCULATION,FreeDrug,BoundDrug,ABSORPTION,EXCRETION,BIOTRANSFORMATION,Thestructureofcellmembrane？Howtotransportit？,Transmembranetransport,ProcedureofpermeatingthroughthevariousbarriersSuchas:variouscellmembranethewallsofthecapillarythewallsoftheintestineblood-brainbarrierplacentalbarrierAbilitythatthedrugpermeatesthroughvariousmembranesTwotypesoftransmembranetransport,Passivetransport(downhillmovement),Accordingtotheconcentrationgradientofthepermeatingdrug,thedirectionofdiffusionwasfromhigherconcentrationtolowerconcentration.Smallmolecules:membraneporesLargemolecules:lipiddiffusionNotrequiringenergyHavingnosaturationHavingnocarriersNotresistingcompetitiveinhibition,Affectingfactors:thesizeofmoleculelipidsolubilitypolaritydegreeofionizationthePHoftheenvironmentsuchas:fluidofbodyfluidincellblood,urine,GenerallyspeakingThedrugswhichareUnionized,lowpolarityandhigherlipidsolubilityareeasytopermeatemembrane.Thedrugswhichareionized,highpolarityandlowerlipidsolubilityaredifficulttopermeatemembrane.,EffectoftheenvironmentPHondrugtransportation,Mostofdrugsareweakacidsorweakbases.Theionizationofdrugsmaymarkedlyreducetheirabilitytopermeatemembranes.ThedegreeofionizationofdrugsisdeterminedbythesurroundingpHandtheirpKa.,Foracids：,Handerson-HasselbalchEquation,ThepKaisthepHatwhichthedrugis50%ionized.,Forbases：,pH和pKa算术差的变化，就会导致解离与非解离药物浓度差的指数变化，因此pH的微小变化将显著的影响药物的解离和转运。,WhenthepHisdifferentfromtheintracellularandextracellularmembraneandthepassivetransportofweakacid/basedrugsareinthebalance,thedrugconcentrationofintracellularandextracellularmembranearecomparedasbelow：,eg.ForweakaciddrugwhosepKaisequalto5.4,unionizedionizedtotal,plasmapH=7.4,GastricjuicepH=1.4,HA1,A-100101,HA1,A-0.00011.0001,Whendrugconcentrationoftheintracellularandextracellularmembranearebalanced,thetotalconcentrationisntequal;whiletheconcentrationofunionizeddrugaresame.,pKa=3.4,WhenthepHoftheintracellularandextracellulararenotequal,thetotalconcentrationofthedruginthetwosidesofmembranearegivenbytheequationasbelow:,Foracid:,Forbase:,Q：WhatkindofdrugscanbeexcretedtothelatexwhichpHistendtoacidity?,Theotherformsofpassivetransport,Filtration:watersolubilitysmallmolecularFacilitatedtransport：（infactitisakindofpassivetransport）TransportfromhighconcentrationtolowconcentrationNotrequiringenergyRequiringcarriersegtheabsorptionofVitaminB12fromGItractThetransportationofGlucosetotheintracellularmembraneofredbloodcells.,Activetransport,permeatingmembranefromlowerconcentrationtohigherconcentration.RequiringenergyRequiringcarriersBeSaturableHavingcompetitiveinhibitionSuchas:peptide,aminoacid,Theconditionswhichneedactivetransport,Na+-K+-ATPaseThetransmitterswereconcentratedinthevesicle.Theexcretionandsecretionofrenaltract,Activetransportcanconcentratedrugsincertainorganortissue(theiodinepump),Diffusion,ActiveTransport,BulkFlow,Endocytosis,IonPair,FacilitatedTransport,Diffusion,ActiveTransport,BulkFlow,Endocytosis,IonPair,FacilitatedTransport,Diffusion,ActiveTransport,BulkFlow,Endocytosis,IonPair,FacilitatedTransport,Diffusion,ActiveTransport,BulkFlow,Endocytosis,IonPair,FacilitatedTransport,Diffusion,ActiveTransport,BulkFlow,Endocytosis,IonPair,FacilitatedTransport,Diffusion,ActiveTransport,BulkFlow,Endocytosis,IonPair,FacilitatedTransport,Sugars,aminoacids,vitamins,Diffusion,ActiveTransport,BulkFlow,Endocytosis,IonPair,FacilitatedTransport,Mostdrugsareabsorbedanddistributedbydiffusion.,Theprocessesofdrugs（ADME）,药物代谢动力学,Pharmacokinetics,Absorption,Distribution,Metabolism,Excretion,“ADME”,movementofdrugsinthebodywhatthebodydoestothedrug,Thedispositiontodrugsbylivingsystemscanbedividedintofourrelatedduration:吸收（Absorption）分布（Distribution）代谢（Metabolism）排泄（Excretion）,ADME系统,Metabolism+Excretion=EliminationAbsorption+Distribution+Excretion=TransportationMetabolism=Transformation,Absorptionisthetransferofadrugfromitssiteofadministrationtothebloodstream.,Characters：Mostofdrugsareabsorbedbythewayofpassivetransport.Intravenousadministrationhasnoabsorption.Theabsorptivespeedaffectsthetimeofappearingeffect.Theabsorptiveextentaffectstheintensityofaction.,Factorsaffectingabsorption:,drugproperties:lipidsolubility、MolecularWeight,polarity,etc.RoutesofAdministration(important):Enteral;parenteralOther:Bloodflowtotheabsorptionsite;TotalsurfaceareaavailableforabsorptionContacttimeattheabsorptionsurfaceAffinitywithspecialtissue,EnteraladministrationOralSublingualRectal,OraladministrationFirstPassElimination(首关消除,首关代谢，首关效应）,Beforethedrugreachesthesystemiccirculation,thedrugcanbemetabolizedintheliverorintestine.AsaResult,theconcentrationofdruginthesystemiccirculationwillbereduced.,FIRSTPASSELIMINATIONMetabolismintheliver,Portalvein,Buccalcavity,Stomach,Intestine,Rectum,Venacava,SublingualAdministration(硝酸甘油),RectalAdministration(水合氯醛),Buccalorrectaladministrationarewaystoby-passtheliverandavoid“firstpass”,Buccal,Rectal,Buccalcavity,Stomach,Intestine,Rectum,Venacava,ParenteralInhalation注射给药静脉内intravenous(IV)肌内intramuscular(IM)皮下subcutaneous(SC)other：intranasal(经鼻给药),intraventricular(心室内给药),Transdermal（经皮给药）,Intravenousadministrationhasnoabsorptionphase.Accordingtotherateofabsorption：InhalationSublingualRectalintramuscularsubcutaneousoraltransdermal,Example:硝酸甘油（Nitroglycerin）,RouteIVSLTransdermal,Onsetimmediate1-3min40-60min,Distribution,Drugdistributionistheprocessbywhichadrugreversiblyleavesthebloodstreamandenterstheinterstitium(extracellularfluid)and/orthecellsofthetissues.,药物的体内过程分布,Factorsaffectingdrugdistribution：BloodflowCapillarypermeabilityCapillarystructureDrugstructueBindingofdrugstoproteinsMostdrugsfoundinthevascularcompartmentareboundreversiblywithoneormoreofthemacromoleculesinplasma.Manyacidicdrugsbindprincipallytoalbumin，whilebasicdrugsfrequentlybindtootherplasmaproteinssuchaslipoproteinsand1-acidglycoprotein(1-AGP)。,药物与血浆蛋白结合（Proteinbinding）Characters：Drugsordinarilybindtoproteininareversiblefashionandindynamicequilibrium.Thoseboundtoproteinarecalledbounddrug,andthoseunboundtoproteinarecalledfreedrug.Onlytheunbounddrugscandiffusethroughthecapillarywall,produceitssystemiceffects,bemetabolizedandbeexcreted.Bounddrugslosepharmacologicalactivitymomentarily，andactasadrugreservoir.Havingsaturationandcompetitiveinhibition.Patientwithlowplasmaprotein(uraemia,hepaticdisease)oroldpeoplewithlowalbumininplasma,theirpercentageofproteinbindingmaybechanged,amountofunbounddrugincreases,effectprecipitate.,interactionWhenthetwokindofdrugsthatpossessthehigherproteinbindingrateareassociatedforclinicalusing,thedruginteractionmayoccur.Iftheamountofunbounddrugdisplacedfromplasmaproteinincreases,theunbounddrugconcentrationandeffectalsoincreases,andperhaps,producetoxicity.Suchas:phenylbutazone(保泰松)Dicoumarin（双香豆素）,Howtosalvagethetoxiceffectofbarbitaldrugs?,WithNaHCO3Alkalizingplasmatoforcetheweakacidicdrug(barbitaldrug)frombraintoplasma.Alkalizingurinetoincreasetheexcretionofthedrugs,Biologicalbarriersbound/ionizeddrugcannotpassthroughtheBBB!,毛细血管内皮细胞联结紧密，管壁外被星型胶质细胞包围。炎症可改变通透性,血脑屏障BloodBrainBarrier,14C-Promazine,14C-PromazineQuaternaryAnalog,+,生物膜屏障（membranebarriers),胎盘屏障Placentalbarriershavingnobarriereffectondrugtransport,butthepregnantwomenshouldespeciallypayattention.,Blood-eyebarriers,Metabolism：mostofteneliminatedbybiotransformationDrugsareand/orexcretionintotheurineorbile.,Theliveristhemajorsitefordrugmetabolism.,Changesaftermetabolism:Thepharmacologicalactivityofthedrugsisdecreasedorlost,whilecertaindrugsmustmetabolizetoexertthereaction.,Twophaseofmetabolism:,PhaseI：oxidation(氧化)、hydrolysis(水解反应)、reduction(还原)Phase：conjugation(结合反应)：glucuronicacid（葡萄糖醛酸）sulfuricacidglycin（甘氨酸）,Varietyofdrugactivityafterbiotransformation:AactivedruginactivemetabolitesBinactivedrugactive/enhancedactivitySuchas:P-450Cyclophosphamide(环磷酰胺)bloodtumoraldophosphamide（醛磷酰胺）Phosphamidemustard（磷酸胺氮芥）,CactivedrugactiveproductPhenacetin非那西丁Acetaminophen(paracetamol)对乙酰氨基酚（扑热息痛）(prototypedrugorparentdrug),DnotoxicorlesstoxicdrugtoxicmetabolitesIsoniazid(Rimifon)AcetylisoniazidINH异烟肼AcetylINHmutagenicity致突变teratogenicity致畸变carcinogenicity致癌hepatotoxicity肝毒性,Econsequent1)Lipophilicxenobiotics(ordrugs)aretransformedtomorepolarandhencemorereadilyexcretableproducts.Lipophilicdrughydrophiliccompound(lipidsolublewatersoluble)2)Largemoleculesmallmolecule,Specialenzyme:AChE,MAOUnspecialenzyme:CytochromeP450Enzymes,Enzymesystemclassification:,properties:lowselectivityandspecificitysaturationlargevariabilityinducedorinhibitedbydrugs-enzymeinductionorenzymeinhibition,Inductionandinhibitionofenzyme,SomedrugscanincreasetherateofsynthesisofcytochromeP450enzymes.Thisenzymeinductioncanenhancetheclearanceofotherdrugs.Inducingagentsare:rifampicin(利福平),carbamazepine（卡马西平),phenobarbital(苯巴比妥),phenytoin(苯妥英),OtherdrugscaninhibitcytochromeP450enzymes.Thisisusuallyseenrapidlyafterdrugexposure.Enzymeinhibitingagentsare:Cimetidine(西咪替丁)chloromycetin（氯霉素）Isoniazid（异烟肼）,excretion,Principalorgans：Kidney，biliarysystem,lungs,intestines,milk,skin,sweatglands,Excretionisatransportprocedurewhichtheprototypedrug(orparentdrug)orothermetabolicproductsareexcretedthroughexcretionorganorsecretionorgan.,RenalExcretion,FiltrationSecretionReabsorption,Renalexcretion,glomerularfiltrationProteinbounddrugsarenotfiltered!Reabsorptionhighlipid-soluble,lowerpolar.unionizeddrugeasytoreabsorbhighwatersoluble,highpolarionizeddruguneasytoreabsorbActivesecretionoftubuleChangingpHoftubularlumenfluid,maychangeabsorptionextentofdruginurine.,acidicurine=alkalinedrugseliminatedaciddrugsreabsorbedalkalineurine=-aciddrugseliminated-alkalinedrugsabsorbedrenaldisease/decreasedclearanceaffectsdrugdosage,affectofuricpHondissociationofdrug,weakaciddrugalkalineurinedissociationlargeexcretionaccelerateweakbasicdrugacidurinedissociationlargeexcretionfastweakaciddrugacidurinedissociationsmallexcretionreduceweakbasicdrugalkalineurinedissociationsmallexcretionslow,competitiveinhibitionwhentwodrugpassthroughsamepathway,usingsamecarrier,competitiveinhibitioncanoccur.Forexample1PenicillinandProbenecidUsingacidpathwayDecreasingexcretionofpenicillinIncreasingactiondurationofenicillin2EthacrynicacidanduricacidDecreasinguricacidexcretionIncreasingaccumulationofuricacidInducinggoutoccur,Initiallypenicillinwasincriticallyshortsupplyprobenecid(丙磺舒)(asimplebenzoicacidderivativewasdevelopedtoblockrapidexcretionofpenicillin)Todayusedasanuricosuricagent(alsopreventsuricacidreabsorption).,forexample:Streptomycin（链霉素）0.5gQ6HHighconcentrationinurinefluid.100timehigherinurinethaninblood.Treatmentinflammationinurictract.SulfonamidesinacidurineConcentrationCrystallization,肠肝循环（hepatoenteralcirculation),liver,bile,gallbladder,GItract,blood,GItractexcretion,HepaticExcretion,Drugscanbeexcretedinbile,especiallywhentheareconjugatedwithglucuronicacid,Drugisabsorbedglucuronidatedorsulfatatedintheliverandsecretedthroughthebileglucuronicacid/sulfateiscleavedoffbybacteriainGItractdrugisreabsorbed(examplesteroidhormones,contraceptives),latexTheconcentrationofbasicdrugsarehigherthanacidicdrugsinthelatex.eg.morphine、Propylthiouracil(丙基硫氧嘧啶)PulmonaryexcretionSweatgland,lacriminal,Part3basicconceptsofpharmacokinetics,Time-concentrationcurveTwokindsofeliminationkineticsCompartmentmodelPharmacokineticsparametersPharmacokineticsofsinglevsmultipledosing,TwolevelsThreedurationsThreepoints,药物消除半衰期（Half-Life，t1/2),Give100mgofadrug1half-life.502half-lives253half-lives.12.54half-lives6.255half-lives3.1256half-lives.1.56,Thetimeittakesforhalfofdrugtobeeliminatedfromthebody.,当仃止用药时间达到5个药物的t1/2时，药物的血浓度（或体存量）仅余原来的3%，可认为已基本全部消除。,5half-lives=97%ofdrugeliminated,Firstorderkinetics,K为消除速率常数，是药动学中的一项重要参数，它并不随时间而发生变化，是药物本身固有的属性。,two-kindsofeliminationkinetics,First-ordereliminationkineticsMorequicklydruginplasmaeliminatesfrombody,higherconcentrationofthedrugis,soitcalledfixedpercentageelimination.fixedhalftime.Iftheconcentrationsunitisexpressedbylogarithm,thec-tcurveisabeeline.Mostofdrugsusedbyclinicaldosagesareeliminatedbyfirstorderkinetics.,Zeroorderkinetics,Theeliminatedratehasnorelationshipwiththedrugconcentration.Thequantityofeliminateddrugsinperunitoftimearefixed.Havingnofixedhalflife.Iftheconcentrationareexpressedbynumericalvalue,theC-tcurveareabeeline.Whendrugsinthebodyareexcessivetoexceedthemaximeliminativeability,thekineticsofthedruginthebodyisaccordingtozeroorderkinetics;whiletheconcentrationdescendstotherangewhichthebodycaneliminate,thekineticswillaccordtofirstorderkinetics.,Charactersofzeroorderkinetics,Zeroorder,Firstorder,Compartmentmodel,Pharmacokineticmodelhavenophysiologicmeaning,butcanbedescribedschematicallyormathematicallyAccordingtoeliminationrateconstant(k)ofdrugindifferenttissueandorgan。,房室模型(compartmentmodel),房室模型(compartmentmodel),Apparentvolumeofdistribution(表观分布容积),Volumeofdistribution(Vd)relatestheamountofdruginthebodytotheconcentrationofdruginbloodorplasma.（L/kg,L）Vd=Dosage/C(plasma),VolumeofDistribution,confinedtoplasma,distributedinbodytissue,Plasma3LBlood5LExtracellularfluid18LTotalbodywater50-60L,Bioavailability（F）：isdefinedasthefractionoftheadministereddrugreachingthesystemiccirculationasintactdrug.Bioavailabiltyishighlydependentonboththerouteofadministrationandthedrugformulation.,绝对生物利用度,相对生物利用度,BIOEQUIVALENCE,Drugsmayhavethesamebioavailability,buttheymaynotbebioequivalent(=havethesamepharmacologicaleffect).,Theformulationofadrugalsoaffectsitsabsorption:,BIOEQUIVALENCE,AUCFormulation1=100mcg/ml/min,AUCFormulation2=100mcg/ml/min,BIOEQUIVALENCE,Drugswithsamebioavailabilitymaynothavethesamebioequivalence.Thisnormallyisnotasimportantaspharmaceuticalcompaniesstate,butitcanbecomeanissuefordrugswithanarrowtherapeuticwindow.,%Oralbioavailability=AUC(po)X100AUC(iv),=50mcg/ml/minX100100mcg/ml/min,=50%,Clearance,Another“constant”thatdesc