超过900个药物的BCS(BDDCS)分类

ResearchArticleBDDCSAppliedtoOver900DrugsLeslieZ.Benet,1,6FabioBroccatelli,1,2andTudorI.Oprea3,4,5Received17May2011;accepted22June2011;publishedonline5August2011Abstract.Here,wecompiletheBiopharmaceuticsDrugDispositionClassificationSystem(BDDCS)classificationfor927drugs,whichinclude30activemetabolites.Ofthe897parentdrugs,78.8%(707)areadministeredorally.Wherethelowestmeasuredsolubilityisfound,thisvalueisreportedfor72.7%(513)oftheseorallyadministereddrugsandadosenumberisrecorded.Themeasuredvaluesarereportedforpercentexcretedunchangedinurine,LogP,andLogD7.4whenavailable.Forall927compounds,theinsilicoparametersforpredictedLogsolubilityinwater,calculatedLogP,polarsurfacearea,andthenumberofhydrogenbondacceptorsandhydrogenbonddonorsfortheactivemoietyarealsoprovided,therebyallowingcomparisonanalysesforbothinsilicoandexperimentallymeasuredvalues.WediscussthepotentialuseofBDDCStoestimatethedispositioncharacteristicsofnovelchemicals(newmolecularentities)intheearlystagesofdrugdiscoveryanddevelopment.TransportereffectsintheintestineandtheliverarenotclinicallyrelevantforBDDCSclass1drugs,butpotentiallycanhaveahighimpactforclass2(effluxinthegut,andeffluxanduptakeintheliver)andclass3(uptakeandeffluxinbothgutandliver)drugs.AcombinationofhighdoseandlowsolubilityislikelytocauseBDDCSclass4tobeunderpopulatedintermsofapproveddrugs(N=53comparedwithover200eachinclasses1–3).TheinfluenceofseveralmeasuredandinsilicoparametersintheprocessofBDDCScategoryassignmentisdiscussedindetail.KEYWORDS:BDDCS;biowaiver;dosenumber;extentofmetabolism;permeabilityrate.In2005,WuandBenet(1)introducedtheBiopharmaceuticsDrugDispositionClassificationSystem(BDDCS).WuandBenetrecognizedthattherewasaverystrongcorrelationbetweentheintestinalpermeabilityrateandtheextentofmetabolism.Forexample,Benetetal.(2)notedthatforthe29drugsandendogenoussubstancesforwhichhumanjejunalpermeabilityratemeasurementswereavailable,therewasanexcellentcorrelationbetweenthesepermeabilityratemeas-urementsandtheextentofdrugmetabolisminhumans.Fourteenofthe16drugsexhibitinghumanintestinalperme-abilityratesgreaterthanmetoprololwereextensivelymetab-olized,while11of12drugsshowingpermeabilityrateslessthanmetoprololwerepoorlymetabolized.Twodrugsshow-ingdisparitybetweenthepermeabilityrateandmetabolism,cephalexinandlosartan,exhibitpermeabilityratesthatdifferbynomorethan16%frommetoprolol(2).Sincethecoefficientsofvariationforthehumanpermeabilityparame-tersrangefrom29%to130%,theseborderlinecompoundsmayinfactalsohavefollowedthecorrelation.Thecorrela-tionbetweentheextentofmetabolismandhumanintestinaljejunalpermeabilitywasmarkedlybetterthanthatobservedforintestinaljejunalpermeabilityandpartitioncoefficientbyTakagietal.(3),whonotedthatLogPmeasuredandcalculatedcorrectlypredicthighversuslowpermeabilityonlyabouttwothirdsofthetime.WuandBenet(1)reasonedthatitmightbeeasiertoutilizemetabolisminassigningdrugclassificationsinceitisdifficultandexpensivetodeterminehumanintestinalpermeabilitiesandsinceitisalsodifficulttoobtainquantitativemassbalancemeasuresthatshow≥90%absorption,theFDAcriterionforabiowaiverasdefinedintheFDABCSGuidance(4),basedontheworkofAmidonetal.(5).Therefore,inproposingtheBDDCSclassificationsystem,WuandBenet(1)substitutedextensiveandpoormetabolismforhighandlowpermeabilityintheBCSwhileutilizingthesamecriteriaastheFDAforhighandlowsolubility.Thatis,ahighsolubilitycompoundatthehighestmarketeddosestrengthwouldbesolublein250mLofwateroverthepHrangeof1–7.5at37°C.UsingtheBDDCS,WuandBenet(1)classified168drugsbasedontheextentofmetabolismandsolubility.ElectronicsupplementarymaterialTheonlineversionofthisarticle(doi:10.1208/s12248-011-9290-9)containssupplementarymaterial,whichisavailabletoauthorizedusers.1DepartmentofBioengineering&TherapeuticSciences,SchoolsofPharmacyandMedicine,UniversityofCaliforniaSanFrancisco,533ParnassusAvenue,RoomU-68,SanFrancisco,California94143-0912,USA.2LaboratoryofChemometrics,DepartmentofChemistry,UniversityofPerugia,ViaElcediSotto,10,60123Perugia,Italy.3SunsetMolecularDiscoveryLLC,1704BLlanoStreet,Suite324,SantaFe,NewMexico87505,USA.4DepartmentofBiochemistryandMolecularBiology,DivisionofBiocomputing,UniversityofNewMexicoSchoolofMedicine,Mailstopcode116145(Albuquerque,NewMexico87131,USA.5CenterforBiologicalSequenceAnalysis,TechnicalUniversityofDenmark,Kemitorvet,Building208,Lyngby2800,Denmark.6Towhomcorrespondenceshouldbeaddressed.(e-mail:[e-mail])TheAAPSJournal,Vol.13,No.4,December2011(#2011)DOI:10.1208/s12248-011-9290-95191550-7416/11/0400-0519/0#2011AmericanAssociationofPharmaceuticalScientistsBDDCSVERSUSBCSAlthoughBDDCSgrewoutoftheFDA’sBCSGuidance(4),WuandBenet(1)proposedBDDCSasameanstopredictthedrugdispositioncharacteristicsofnovelchemicals(here,referredtoas“newmolecularentities”,NMEs)duringtheearlystagesofdrugdiscoveryanddevelopment.Suchexampleswillbediscussedbelow.Recently,BenetandLarregieu(6)reviewedthedifferencesbetweenBCSandBDDCSintermsofpurposeandbasis.ThepurposeofBCSistofacilitatebiowaiversofinvivobioequivalencestudiesfordrugsthatexhibitnosignificantintestinalabsorptionp