pharmacology药理学浙江大学教学信息化平台.pptx

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1、KineticsKineticsModelsModelsParameterParameters s第1页/共81页2.Transport of Drug in the BodyMechanisms of drug permeation across cell Mechanisms of drug permeation across cell membranemembraneA.aqueous channels in the intercellular junctionsB.B.lipid lipid cell cell membranemembranes s C.C.carriers carr

2、iers(transporters)(transporters)(into or out of(into or out of cells)cells)D.D.endocytosisendocytosis exocytosisexocytosis 第2页/共81页 2.1 Transmembrane Transport of Drugs2.1 Transmembrane Transport of Drugs(1)Non-carrier Transport(1)Non-carrier Transport Simple diffusionSimple diffusion（简单扩散简单扩散简单扩散简单

3、扩散/单纯扩散单纯扩散单纯扩散单纯扩散）FiltrationFiltration（滤过滤过滤过滤过）第3页/共81页(2)Carrier-mediated Transport(2)Carrier-mediated Transport a.Active transporta.Active transport Characteristics of active transportCharacteristics of active transport Involving specific carrier(Involving specific carrier(transportertransporte

4、r)Energy-dependent Energy-dependent Saturability Saturability Competition at same carrier Competition at same carrier Moving Moving against against concentration concentration gradient gradient(up-hill)(up-hill)第4页/共81页b.Facilitated diffusion（易化扩散易化扩散易化扩散易化扩散）(transporter-mediated diffusiontransport

5、er-mediated diffusion)Involving specific carriers(Involving specific carriers(transportertransporter)Energy-independent Energy-independent Saturability Saturability Competition with other drugs Competition with other drugs Concentration gradient(down-hill)Concentration gradient(down-hill)(3)Endocyto

6、sis/exocytosis（入入入入胞胞胞胞/出出出出胞胞胞胞）第5页/共81页Another classificationPassive transportSimple diffusionSimple diffusion（简单扩散简单扩散简单扩散简单扩散/单纯扩散单纯扩散单纯扩散单纯扩散）FiltrationFiltration（滤过滤过滤过滤过）Facilitated diffusionFacilitated diffusion（易化扩散易化扩散易化扩散易化扩散）Active transportActive transport(Active transport(主动转运主动转运主动转运主

7、动转运)Pinocytosis/exocytosisPinocytosis/exocytosis（入入入入胞胞胞胞/出出出出胞胞胞胞）第6页/共81页A.Simple diffusionMost drugs are weak acids or bases.Their diffusion passing through cell membrane depends the lipid-soluble state(un-ionized form)第7页/共81页 Determinants of simple diffusionDeterminants of simple diffusion For

8、most drugs of small molecules(usually are weak acids or weak For most drugs of small molecules(usually are weak acids or weak bases):bases):Lipid-soluble or un-ionized formsLipid-soluble or un-ionized forms pKa pKa of the drug andof the drug and pHpH of the body fluidof the body fluid TheThe pKapKa

9、is the pH at which the is the pH at which the concentrations of the ionized and un-concentrations of the ionized and un-ionized forms are equal.ionized forms are equal.第8页/共81页 Henderson-Hasselbalch equationHenderson-Hasselbalch equation Weak acid drugs:Weak acid drugs:p pH-H-p pKa=log(AKa=log(A-/HA

10、)/HA)p pKa-Ka-p pH=log(HA/AH=log(HA/A-)Weak base drugs:Weak base drugs:p pKa-Ka-p pH=log(BHH=log(BH+/B)/B)p pH-H-p pKa=log(B/BHKa=log(B/BH+)第9页/共81页 pHpKaun-ionized un-ionized formformlipid-lipid-solublesolubleSimple Simple diffusiondiffusionWeak acidsWeak basesAnd/orAnd/orAnd/orAnd/orAnd/orAnd/orAn

11、d/orAnd/or第10页/共81页Three types of functional membrane proteins.B.Carrier(transporter)-mediated transport第11页/共81页Models of transmembrane transport across the lipid bilayerModels of transmembrane transport across the lipid bilayer第12页/共81页 2.2 Free and Bound Forms2.2 Free and Bound Forms Plasma prote

12、in bindingPlasma protein binding Tissue/organ affinity Tissue/organ affinity第13页/共81页3.Fate of the drug in the body Absorption Distribution Metabolism(Biotransformation)(Biotransformation)Excretion ADMEADME第14页/共81页3.1 AbsorptionAbsorption Absorption is is the the transfer transfer of of a a drug dr

13、ug from from its its site of administration to the blood stream.site of administration to the blood stream.Gastrointestinal tract Parenteral injection -i.m.,s.c.Inhalation Transdermal 第15页/共81页(1)Gastrointestinal tractRoute:OralOral Sublingual Sublingual Rectal RectalAbsorption sites:Oral Oral Gastr

14、icGastric Intestinal Intestinal Rectal Rectal第16页/共81页Factors influencing absorption:blood flow to the absorption siteblood flow to the absorption site total total surface surface area area available available for for absorptionabsorption contact time at the absorption surface contact time at the ab

15、sorption surface physic-chemical properties of the drug physic-chemical properties of the drug first-pass eliminationfirst-pass elimination第17页/共81页(2)Parenteral injection intramuscular injection(i.m.)intramuscular injection(i.m.)subcutaneous injection(s.c.)subcutaneous injection(s.c.)DeterminantsDe

16、terminants Local blood flow;Solubility of the drug Local blood flow;Solubility of the drug (3)Others Inhalation;Intranasal;Inhalation;Intranasal;Transdermal;Topical Transdermal;Topical第18页/共81页3.2 DistributionDrug Drug distribution distribution is is the the process process by by which which a a dru

17、g drug reversibly reversibly leaves leaves the the blood blood stream stream and and enters enters the the interstitium interstitium(extracellular(extracellular fluid)and/or the cells of the tissues.fluid)and/or the cells of the tissues.Blood flow-dependent phase of distribution Blood flow-dependent

18、 phase of distribution Selective distribution Selective distribution Tissue-plasma Tissue-plasma balance:balance:importance importance of of measuring measuring plasma plasma concentrationconcentration第19页/共81页(1)Binding of drug to plasma proteins Bound drug:can not distribute/inactive temporallycan

19、 not distribute/inactive temporallyreversible reversible(storage(storage form)form)/percentage percentage of of bindingbindingplasma protein capacityplasma protein capacitycompetitive displacementcompetitive displacement 第20页/共81页 (2)(2)Physic-chemical Physic-chemical properties properties of of the

20、 the drugdrug (3)Blood flow and re-distribution (3)Blood flow and re-distribution (4)Affinity to organs or tissues (4)Affinity to organs or tissues (5)Barriers (5)Barriers Blood-brain barrier(BBB)Blood-brain barrier(BBB)Placental barrier Placental barrier Blood-eye barrier Blood-eye barrier 第21页/共81

21、页 Blood-brain barrier(BBB)Blood-brain barrier(BBB)Able to pass throughAble to pass through Unable to pass throughUnable to pass through Small molecules Small molecules Large moleculesLarge molecules Lipid-solubleLipid-soluble Water-solubleWater-soluble Transporter-mediation Transporter-mediation Amo

22、unt of drug passing through BBBAmount of drug passing through BBB Increases Increases when when inflammation inflammation oror larger larger doses doses usedused第22页/共81页Placental barrier:More permeable Drugs for pregnant women:Drugs for pregnant women:A,BA,B relatively safe relatively safeC C-cauti

23、on-cautionD,D,X X-toxic-toxic第23页/共81页3.3 Metabolism(biotransformation)Drug Drug metabolism metabolism is is the the process process transforming transforming lipophilic lipophilic drug drug into into more more hydrophilic hydrophilic metabolites,metabolites,which which is is essential essential for

24、 for the the elimination elimination of of these these compounds from the body and termination of their biological activitycompounds from the body and termination of their biological activity.(1)Metabolism sites(1)Metabolism sites Liver:Liver:for most of the drugsfor most of the drugs Other organs/t

25、issuesOther organs/tissues:intestine,kidney,intestine,kidney,lung,plasma,lung,plasma,etcetc.第24页/共81页 (2)Phases of metabolism(2)Phases of metabolism Phase Phase I:I:Oxidation,Oxidation,reduction,reduction,hydrolysishydrolysis most drugs are inactivatedmost drugs are inactivated few(few(prodrugsprodr

26、ugs)is activated)is activated Phase II:Phase II:ConjugationConjugation inactivated inactivated Metabolites:Metabolites:more water-soluble easier to excretemore water-soluble easier to excrete第25页/共81页第26页/共81页(3)Enzymes in drug metabolism Enzymes in Phase I:cytochrome-P450,450,such as such as CYP2A6

27、,CYP3A4CYP2A6,CYP3A4 many other enzymes Enzymes in Phase II:acetylase glucuronosyltransferase etc.第27页/共81页 Induction of hepatic enzymes by drugs example:example:phenytoinphenytoinsteroids,nifedipinesteroids,nifedipineInhibition of hepatic enzymes by drugs example:example:verapamilverapamildiazepamd

28、iazepam第28页/共81页3.4 ExcretionRemoval Removal of of a a drug drug from from the the body body via via a number of routes.a number of routes.Elimination of drugs from the bodyAction on excretory organs第29页/共81页3.4 Excretion(1)Excretion routes Kidney-Kidney-renal excretionrenal excretion Bile Bile(hepa

29、to-enteral circulation)(hepato-enteral circulation)Lung Lung GI tract GI tract MilkMilk Secretion glands Secretion glands第30页/共81页3.5 Elimination and AccumulationEliminationElimination（消除消除消除消除）MetabolismMetabolism Excretion Excretion Distribution(stored in fat,hair,etc)Distribution(stored in fat,ha

30、ir,etc)AccumulationAccumulation（蓄积蓄积蓄积蓄积）Dosing rate elimination rate Dosing rate elimination rate 第31页/共81页 1.1.Drug concentration-time curve Drug concentration-time curve (C-T curve)(C-T curve)2.2.Kinetic rate processesKinetic rate processes 3.Pharmacokinetic models3.Pharmacokinetic models 4.4.Pha

31、rmacokinetic parameters and their Pharmacokinetic parameters and their implicationsimplicationsKinetic ProcessesKineticsKineticsModelsModelsParameterParameters s第32页/共81页1.1.Drug Drug concentration-time concentration-time curvecurve (C-T(C-T curve)curve)Maximal(peak)concentration:Maximal(peak)concen

32、tration:CmaxCmax oror CpCp Time to maximal concentration(Peak time):Time to maximal concentration(Peak time):TmaxTmax or or TpTp Area under the curve:Area under the curve:AUCAUC Multiple dosing(steady state):Multiple dosing(steady state):Css max,Css min,CssCss max,Css min,CssKinetic Processes第33页/共8

33、1页tCi.m.i.m.s.c.s.c.OralOrali.v.i.v.CmaCmax xCpCp Tmax,TpTmax,Tp第34页/共81页Tmax,Cmax and AUCTmax,Cmax and AUCTmaxCmax AUCCt第35页/共81页C-T curve after multiple dosingC-T curve after multiple dosing(same dose and interval)(same dose and interval)在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度，并维持在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度

34、，并维持在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度，并维持在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度，并维持在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓度，用度，用度，用度，用CssCss表示表示表示表示 第36页/共81页2.Kinetic rate processes dC/dt KCn第37页/共81页 2.1 Zero order kinetics2

35、.1 Zero order kinetics n n 0 0 dC/dt dC/dt K K C Ct t C C0 0K tK t C C0 0C Ct t K tK t when C when Ct t1/2 C1/2 C0 0,t=t=t t1/21/2 thenthen,0.5 C,0.5 C0 0 K K t t1/21/2 t t1/21/20.5 C0.5 C0 0/K/K第38页/共81页 Zero order kineticsZero order kineticsA.A.same amounts of same amounts of drug aredrug are elim

36、inated per unit eliminated per unit timetimeB.B.t t1/21/2 is not a constant is not a constantC.C.C-T curve is linear C-T curve is linearD.D.no Css theoretically no Css theoretically第39页/共81页Kinetic properties of C-T curves after single bolus Kinetic properties of C-T curves after single bolus inject

37、ion of druginjection of drug第40页/共81页 2.2 First order kinetics2.2 First order kinetics n n 1 1 dC/dt dC/dt KCKC C Ct t C C0 0e e KtKt lnC lnCt t lnClnC0 0Kt Kt KtKtlnClnC0 0lnClnCt tln(Cln(C0 0/C/Ct t)when C when Ct t1/2C1/2C0 0，t tt t1/21/2，thenthen t t1/21/2ln2/Kln2/K第41页/共81页 First order kinetics

38、First order kinetics A.A.eliminated eliminated at at same same rate rate per per unit time unit time B.B.t t1/21/2 is a constant is a constantC.C.logC-T curve is linear logC-T curve is linearD.D.steady steady state state(Css)(Css)after after 4-5 4-5 t t1/21/2 第42页/共81页Kinetic properties of C-T curve

39、s after single Kinetic properties of C-T curves after single bolus injection of drugbolus injection of drug第43页/共81页 2.3 Non-linear kinetics2.3 Non-linear kineticsHigher Higher concentration concentration(or or larger larger dosedose):):zero order kineticszero order kineticsLower Lower concentration

40、 concentration(or or smaller smaller dosedose):):first order kineticsfirst order kineticsBecause Because of of limits limits in in elimination elimination capacity capacity Examples:Examples:aspirin,aspirin,phenytoin,phenytoin,ethanolethanol Confirmation:Confirmation:different different t t1/21/2 wh

41、en when given given different dosesdifferent doses第44页/共81页 Michaelis-Menten kineticsMichaelis-Menten kinetics dC/dt=Vmax dC/dt=Vmax C/(Km+C)C/(Km+C)if if Km CKm C dC/dt=Vmax dC/dt=Vmax C/Km C/Km Vmax Vmax/Km Km=Ke Ke First orderFirst order if if C KmC Km dC/dt=Vmax dC/dt=Vmax C/C C/C dC dC/dt dt=-V

42、max-Vmax Zero Zero orderorder第45页/共81页Kinetic properties of C-T curves after single Kinetic properties of C-T curves after single bolus injection of drugbolus injection of drug第46页/共81页Kinetic properties of C-T curves after Kinetic properties of C-T curves after single dose of aspirinsingle dose of

43、aspirin第47页/共81页3.Pharmacokinetic modelsOne-compartment modellogCtiv第48页/共81页 3.2 Two-compartment model3.2 Two-compartment modelFirst,enter the central First,enter the central compartmentcompartmentThen,distributed to peripheral Then,distributed to peripheral compartment,and eliminatedcompartment,an

44、d eliminated1 12 22,32,3第49页/共81页logCtiviv logC-T curvelogC-T curveDistributionDistributionEliminationEliminationt1/21/2 t1/2 1/2 第50页/共81页4.Pharmacokinetic parameters and their implications 4.1 Bioavailability(F)BioavailabilityBioavailability is the fraction of is the fraction of administered drug(

45、oral)that reaches the administered drug(oral)that reaches the systemic circulationsystemic circulation第51页/共81页Absolute bioavailability（绝对生物利用度绝对生物利用度绝对生物利用度绝对生物利用度）F=AUC(po,(po,sc,imsc,im)/AUC(iv)(iv)Relative bioavailability（相对生物利用度相对生物利用度相对生物利用度相对生物利用度）F=AUC(tested)(tested)/AUC(standard)(standard)

46、Implication:Implication:Evaluation for absorption and Evaluation for absorption and drug quality controldrug quality controlInfluence:Influence:Absorption rateAbsorption rate;First-pass First-pass eliminationelimination第52页/共81页CtAUC(po)AUC(iv)Absolute bioavailability:Absolute bioavailability:F=AUC(

47、po)/AUC F=AUC(po)/AUC(iv)(iv)第53页/共81页4.2 Apparent volume of distribution(Vd d)The The volume of distribution(Vvolume of distribution(Vd d)relates the relates the amount of drug in the body(D)to the amount of drug in the body(D)to the concentration of drug(C)in the blood or concentration of drug(C)i

48、n the blood or plasmaplasma.i.v.Vd d=D/C p.o.Vd d=FD/C第54页/共81页4.3 Half-life(t1/2)/elimination constant(elimination constant(KeKe)The The half-life(half-life(t1/21/2)is the time takes for the is the time takes for the plasma concentration or the amount of drug in plasma concentration or the amount o

49、f drug in the body reduced by 50%.the body reduced by 50%.t1/2=0.693/Ke Vd/Cl (First-order kinetics,for most cases)(First-order kinetics,for most cases)KeKe:A A constant fractionconstant fraction of drug in the body is eliminated per unit of time of drug in the body is eliminated per unit of time(fi

50、rst-order kineticsfirst-order kinetics).).第55页/共81页Implications of t1/21/2 Elimination rate Elimination rate Estimating the times of fully elimination Estimating the times of fully elimination and reaching steady stateand reaching steady state Classifying short-and long-acting drugs Classifying shor