给药体积血样采集量

AGoodPracticeGuidetotheAdministration

ofSubstancesandRemovalofBlood,

IncludingRoutesandVolumesJOURNALOFAPPLIEDTOXICOLOGYJ.Appl.Toxicol.21,15–23(2001)Keywords:bloodvolumes;bloodremoval;administrationsubstances;laboratoryanimals;refinement.objectivesThisarticleistheresultofaninitiativebetweentheEuropeanFederationofPharmaceuticalIndustriesAssociations(EFPIA)andtheEuropeanCentrefortheValidationofAlternativeMethods(ECVAM).Itsobjectivesaretoprovidetheresearcherinthesafetyevaluationlaboratorywithanup-to-date,easyto-usesetofdatasheetstoaidinthestudydesignprocesswhilstatthesametimeaffordingmaximumwelfareconsiderationstotheexperimentalanimals.objectives(i)toprovideaguideonadministrationvolumesforuseincommonlaboratoryspeciesusedintoxicitystudiesrequiredbyregulatoryauthorities;(ii)toprovideconsensusdosagelevelsforroutineusethatrepresentgoodpracticeintermsofanimalwelfareandpracticality;(iii)toproduceaguidetodosagelevelsrepresentingtheupperlimitofcommonpractice,whichleavesscopetomakethecaseforspecialinvestigations.Oralroute.Onoccasions,itmaybenecessarytorestricttheanimals’foodintakebeforedosing.Thisfactormayaffectabsorption.Largedosevolumes(40mlkg-1)havebeenshowntooverloadthestomachcapacityandpassimmediatelyintothesmallbowel.5Largervolumesmayalsorefluxintotheoesophagus.Thedurationoffastingwilldependuponthefeedingpatternofthespecies,thestartingtimeforfoodrestriction,thephysiologyofthespecies,thelengthoftimeofdosing,dietandthelightcycle.6Itisrecommendedthatforaccuracyofdosingandtoavoiddosingaccidentsliquidsareadministeredbygavage.Parenteralroutes.肠道外给药

Forsubstancesadministeredparenterallythedosevolumeusedstabilityoftheformulationbeforeafteradministration,pH,viscosity,osmolality,bufferingcapacity,sterilityandbiocompatibilityoftheformulationarefactorstoconsider.Thisisparticularlyimportantformultipledosestudies.ThesefactorsarereviewedinsomedetailbyClaassen.7Thesmallestneedlesizeshouldbeused,takingintoaccountthedosevolume,viscosityofinjectionmaterial,speedofinjectionandspeciesSubcutaneous.皮下Thisrouteisfrequentlyused.Therateandextentofabsorptiondependontheformulation.Intraperitoneal.腹腔Thisrouteisusedinfrequentlyformultipledosestudiesbecauseofpossiblecomplications.Thereisapossibilityofinjectingintotheintestinaltractandirritantmaterialsmaycauseperitonitis.Drugabsorptionfromtheperitonealcavityaftertheadministrationofthecompoundasasuspensionisdependentonthepropertiesofthedrugparticlesandthevehicle,andthedrugmaybeabsorbedintobothsystemicandportalcirculations.Table1.Administrationvolumesconsideredgoodpractice(andpossiblemaximaldosevolumes)Intramuscular.Intramuscularinjectionsmaybepainfulbecausemusclefibresarenecessarilyplacedundertensionbytheinjectedmaterial.Sitesneedtobechosentominimizethepossibilityofnervedamage.Sitesshouldberotatedformultipledosestudies.Adistinctionneedstobemadebetweenaqueousandoilyformulationswhenspeedofabsorptionisimportant(oilyformulationsarelikelytoremainasadepotfor.24h).Withmultipledosestudiesthereisaneedtoconsidertheoccurrenceofinflammationanditssequelae后遗症.IntravenousadministrationInmoststudiesusingtheintravenousroutethetestsubstanceisgivenoverashortperiodofapproximately1min.Suchrelativelyrapidinjectionsrequirethetestsubstancetobecompatiblewithbloodandnottooviscous.Whenlargevolumesarerequiredtobegiven,theinjectionmaterialshouldbewarmedtobodytemperature.Therateofinjectionisanimportantfactorinintravenousadministrationanditissuggestedthat,forrodents,therateshouldnotexceed3mlmin-1.Nodetectablechangesinhaematocritorheartratewereobservedindogsfollowingrapidintravenousinjectionof6mlkg-1saline,but20mlkg-1wasassociatedwith15%haemodilutionandatransienttachycardia(up46%over1min).血液稀释和一过性心动过速SlowintravenousinjectionBecauseoftheexpectedclinicalapplicationofthecompound,orbecauseoflimitingfactorssuchassolubilityorirritancIthasbeenshownthatratsmaybegivendailyintravenousinjectionsofisotonicsalineatdosagesupto80mlkg-1at1mlmin-1for4dayswithoutsignificantsignsofdistressorpulmonarylesions.9However,pulmonarylesionsincreasedinincidenceandseveritywhenthedurationoftreatmentincreasedto30daysandtheinjectionwasadministeredateither0.25,0.5or1.0mlmin-1.Theremaywellhavebeenadverseeffectsatanearliertimepointbutthepathologyhadnothadtimetodevelop.Continuousinfusion.Forsimilarreasonsofsolubilityorclinicalindicationitmaybenecessarytoconsidercontinuousinfusion,butcarefulconsiderationisneededifinfusionsareprolonged.Thevolumeandrateofadministrationwilldependonthesubstancebeinggivenandtakeaccountoffluidtherapypractice.Asaguide,thevolumeadministeredonasingleoccasionwillbe,10%ofthecirculatingbloodvolumeover2h.Intradermal.Thissiteistypicallyusedforassessmentofimmune,inflammatoryorsensitizationresponseMaterialmaybeformulatedwithanadjuvant（免疫佐剂）.Volumesof0.05–0.1mlcanbeused,dependentuponthethicknessoftheskin.Repeatedintravenousinfusion:dosevolumes/rates(andpossiblemaximalvolumes/rates)BloodsamplingvolumesTable4.LimitvolumesandrecoveryperiodsTable5.Totalbloodvolumesandrecommendedmaximum

bloodsample