药代动力学参数

PharmacokineticsandItsRoleinSmallMoleculeDrugDiscoveryResearchGrahamR.Jang,RobertZ.Harris,DavidT.LauDepartmentofPharmacokineticsandDrugMetabolism,AmgenInc.,ThousandOaks,California!Abstract:Pharmacokinetics(PK),whichdescribesthedispositionofadruginthebody,shouldbeaprimaryconsiderationintheselectionofadrugcandidate,ultimatelycontributingtoitseventualclinicalsuccessorfailure.Accordingly,asoundunderstandingofPKconceptsandanappreciationofthejudicioususeofPKandrelated(e.g.,metabolism,transporter)dataindrugdiscoverycanbebene®cialtothoseinvolvedintheprocess.Thisreviewde®nesimportantPKparameters(e.g.,clearance,volumeofdistribution,half-life),describesmethodsofPKdataanalysis(noncompartmentalvs.compartmental)andprovidesanoverviewofadditionalconceptssuchasallometricscaling,PK/pharmacodynamicmodeling,andnonlinearPK.Furthermore,theroleandstrategicuseofPKscreensindrugdiscoveryarediscussed.ß2001JohnWiley&Sons,Inc.MedResRev,21,No.5,382±396,2001Keywords:Pharmacokinetics;noncompartmentalpharmacokinetics;compartmentalpharmaco-kinetics;drugdiscovery;ADME1.INTRODUCTIONPharmacokinetics(pharmaco-drug,kinetics-movement)isthesciencethatdescribesthemovementofdrugsinthebody.Asopposedtopharmacodynamics,whichdescribeswhatthedrugdoestothebody,pharmacokinetics(PK)describeswhatthebodydoestothedrug.TherearefourmajordeterminantsofPK,commonlyreferredtoasADME(absorption,distribution,metabolismandexcretion).Absorptiondescribestheprocessbywhichdrugmoleculesmovefromthesiteofadministrationtothesystemiccirculation.Becausethemajorityofsmallmoleculetherapeuticsaredesignedfororaladministration,dissolutionandtheabilitytopermeatethegastrointestinaltractoftenpresentthe®rstmajorbarrierstosystemicdrugavailability.Distributiondescribesthemovementofdrugmoleculesfromthesystemiccirculationtoextravascularsites.Giventhatmostdrugtargetsarenotinthevasculature,access382Correspondenceto:DavidT.Lau,PharmacokineticsandDrugMetabolism,AmgenInc.,OneAmgenCenterDrive,ThousandOaks,CA91320^1799.(E-mail:[e-mail])MedicinalResearchReviews,Vol.21,No.5,382^396,2001ß2001JohnWiley&Sons,Inc.totargetorganscommonlyreliesondrugdistribution.Forexample,foradrugtobeactiveinthecentralnervoussystem,itmustpenetratetheblood±brainbarrier.Metabolismdescribestheenzymaticbreakdownofadrug.Itfrequentlyservesastheprimarydefensemechanismbywhichthebodyattemptstoavoidexposuretoxenobiotics.Typically,drugmoleculesareconvertedtomorehydrophilic,inactivemetabolites,whicharesubsequentlyexcretedfromthebody.However,metabolitescancontributetodrugactivityortoxicity.UnderstandingthepathwaythroughwhichacompoundismetabolizedandthePKofitsmetabolitesisessentialforthesuccessfuldevelopmentofadrugcandidate.Finally,excretiondescribespassiveoractivetransportofdrugmoleculesintotheurineorbile.Duringthelastfewyears,noveltransportersmediatingdrugexcretionhavebeenidenti®edanditislikelythattheirrolesincontrollingdrugdispositionwillbecomebetterde®nedinthenearfuture.ScientistsindrugdiscoveryresearchshouldappreciatethatanidealdrugcandidatepossessesbothgoodpharmacologicalactivitiesaswellasgoodPKproperties.Forexample,withoutthelatter,theeffectofapotentmoleculemaybesoshort-livedthatitsclinicalbene®tsmaybeminimal.Inthelastdecade,theimportanceofearlyPKscreeninghasbecomewell-recognizedinthepharmaceuticalindustry.GreaternumbersofinvitroandinvivoPKscreeningstudiesareperformedinanefforttooptimizethePKpropertiesandpotencyofadrugcandidateinparallel.Figure1summarizescommonissuesindrugdiscoverythatariseduetoundesirableADMEproperties,andsomeofthescreensthataretypicallyusedtoevaluatetheseproperties.Thesescreensarevaluabletoolsthathelpexpeditecompoundselectioninleadoptimization.Inaddition,Figure1.Potentialsmallmoleculedrugdiscoveryissuesandexperiments(italicized)frequentlyemployedtoaddressthem.ROLEOFPKINSMALLMOLECULEDRUGDISCOVERYRESEARCH*383assessmentofthePKpropertiesofdrugcandidatesinanimalsiscrucialindrugdiscovery,forreasonsnotedbelow.Becauseofthis,itisimportantthatthoseleadingdrugdiscoveryteamspossessasoundunderstandingoffundamentalPKconceptsandthesigni®canceandutilityofPKdataindrugdiscovery.2.COMPONENTSOFAPKSTUDYAPKstudyconsistsofanin-lifephase(dosingandsamplingofanimalsorsubjects),abioanalyticalphase,andanalysisoftheresultingblood,plasma,orserumconcentrationversustimedatausingnoncompartmentalorcompartmentalPKmethods.AlthoughthefocusofthisworkisdescribingPKconceptsandanalysismethods,afewcommentsontheplanningandconductofthein-lifeandbioanalyticalphasesarewarranted.Indrugdiscovery,initialPKstudiesaremostcommonlyconductedinrodentsand/orthespeciesusedfortheassessmentofinvivoef®cacy.Subsequently,experimentsinalargeanimalspeciessuchasdogormonkeyareperformedtobetterdescribethedispositionofacompound(inmultiplespecies),supporttoxicologystudies,andgeneratedatausefulinpredictinghumanPKparameters(seediscussiononscalingbelow).Itshouldbenotedthatlowaqueoussolubilityofdiscoverymoleculesoftennecessitatessigni®cantformulationworkpriortodosing.Therouteofcompoundadministrationisgenerallydictatedbythatwhichwillbestensureclinicalandcommercialsuccessforagive