第二章

藥物代謝動力學

Pharmacokinetics南開大學醫學院張京玲韓姍Pharmacokinetics目的掌握藥代動力學的基本概念及基本參數的計算。了解藥代動力學的基本房室模型及血藥濃度測定的臨床意義。

Pharmacokinetics內容一級動力學與零級動力學衰減原理。藥物的跨膜轉運機理與影響因素。藥物吸收途徑，第一關卡消除，肝腸循環，生物利用度，血漿蛋白結合原理與意義，藥物分布不均勻性的原因與意義，表觀分布容積，藥物體內轉化過程及代謝產物，肝臟微粒體藥物代謝酶（肝藥酶及P450）的特性，誘導與抑制，藥物作用的消除即代謝，排泄與儲存。藥物消除速率常數與藥物消除率的概念。藥物排泄途徑與機理，藥物時效關系曲線，藥物血漿半衰期，連續用藥時藥物在體內的蓄積，穩態血濃度與首劑速效劑量。藥物血漿濃度監測的應用。PharmacokineticsDispositionofdrug(ADMEsystem)Time-concentrationrelationshipEliminationkineticsTheEndDispositionofdrug

DrugtransportAbsorptionDistributionMetabolismorBiotransformationExcretion

Drugtransport

TypeFeatureInfluencefactor①Con.gradient;②carrier;energy;③saturable;④competitiveinhibit;①FiltrationPassive②Simplediffusiontransport

Carrier-mediated

transportFacilitateddiffusion

ActivetransportComparison!①Molecularweight(M.W.)②LiposolublepropertyorPolarity③Ionizationdegreea.pHb.pKaFeatureFeature

Passivetransport

Activetransport

Anothername

DescendingtransportAscendingtransportConcentration&electrochemicalgradient

ObeyAgainst

Needspecialcarrier

No

Yes

FeatureFeature

Passivetransport

Activetransport

Needenergy

No

Yes

Saturable

No

Yes

Competitiveinhibit

NoYesTypesofdistribution

Simplediffusion&filtrationRenaltubules,neuron,livercells

Featuredby

Mostdrugs

Fewdrugs

InfluencefactorEffectMolecularweightLiposolublepropertyPolarityionizationdegree(PH&Pka)EasytotransportSmallHighLowNon-dis-associatedHardtotransportLargeLowHighDis-associatedHanderson-HasselbalchequationAbsorptionConceptRouteSpeedDegreeInfluencefactor①P.O(peros,ororal)

First-passelimination②I.V(intravenous)③I.M(intramuscular④S.C(subcutaneou⑤P.r(perrectum)⑥Inhalation;sublingual;Lungs＞tongue＞rectum＞im＞sc＞po＞skin;Lungs＞tongue＞rectum＞im＞sc＞po＞skin;M.W.HydrophilicorlipophilicpHBloodflowDistributionConceptInfluencefactor①PlasmaproteinbindingFeatureResultSignificance②BarrierBlood-brainbarrier(BBB)PlacentabarrierBlood-eyebarrierMetabolismConceptPhase

ResultEnzymeEnzymeinduction①PhaseⅠoxidations,reductions,hydrolysis；②PhaseⅡconjugationsSpecialenzymeNon-specialenzyme(hepaticmicrosomalmixedfunctionoxidasesystem)CytochromeP-450NADPHFlavoproteinInducersInhibitorsActivity↑or↓Toxicity↑or↓ExcretionConceptRouteKidneyFiltrationExcretionBileHepatoenteralcirculationMilkSalivaSkinLungsTime-concentrationcurve

timeMetabolismandeliminationphaseCmaxLatentperiodContinuanceperiodRemnantperiodMTCMECTmaxDrugconcentration(mg/L)AbsorptionanddistributionphaseTime-concentrationrelationshipCmaxCmaxTpeakEliminationkineticsEliminationkineticsZero-orderkineticsConceptFormulaCt=C0–Kt;0.5C0=C0–Kt1/2figureFeatureSignificanceEliminationkineticsFirst-orderkineticsConceptFormulaFigureFeaturesignificanceEliminationkineticsCompartmentmodelOne-compartmentmodelTwo-compartmentmodelThree-compartmentmodelEliminationkineticsParametersBioavailability,(F)AbsoluteFRelativeF

AUC(P.O.）AUC(I.V.）AbsoluteF = ×100%

RelativeF= ×100%(AUC：Areaunderthecurve)BiologicalEquivalentTrial

AUC(trial）AUC(standard）EliminationkineticsApparentvolumeofdistribution,(Vd)DefinitionFormula：ClinicalsignificanceEliminationkineticsEliminationrateconstant,(Ke)Half-life,(t1/2)ConceptFormulaClinicalsignificanceEliminationkineticsAreaundercurve,(AUC)formulaClearance,(Cl)DefinitionFormulaClinicalsignificanceClmeansthetotalrateoftheeliminationofthedrugsbytheliverandthekidney.Itdoesn’tequaltotheeliminationspeedofthedrugs(RE).Ithasnothingtodowiththedoseofdrugs(A),butisinfluencedbythestateoftheliverandkidney.EliminationkineticsSteadystateorPlateau,(Css)CmaxTpeakDoseLoadingdose(D1)Maintenancedose(DM)P.O.I.V.練習t1/2為8h,按一級動力學消除的藥物，95%被排出體外需多長時間?2.某藥在體內按一級動力學消除，在其吸收達高峰后兩次抽血，其血藥濃度分別為180ug/ml、22.5ug/ml，兩次抽血間隔9小時，該藥的血漿半衰期是多少？1、字體安裝與設置如果您對PPT模板中的字體風格不滿意，可進行批量替換，一次性更改各頁面字體。在“開始”選項卡中，點擊“替換”按鈕右側箭頭，選擇“替換字體”。（如下圖）在圖“替換”