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Prediction of Human Lethality of Psychoactive Drugs from Rodent

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Prediction of Human Lethality of Psychoactive Drugs from Rodent International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019 Prediction of Human Lethality of Psychoactive Drugs From Rodent LD50 Values John C. Dearden, Liverpool John Moores University, UK ABSTRACT Thenumberofdeathsfromtheabuseofpsychoactivedrugsisincreasingyearafteryear,andnew designerpsychoactivedrugsofunknowntoxicityfrequentlyappearonthestreets.Humanlethaldrug dosesgenerallydonotcorrelatewellwithanimalLD50values.Inordertoinvestigatewhetherthat holdsforpsychoactivedrugs,humanlethaldosevaluesandratandmouseLD50valuesforseveral routesofadministrationforeighteensuchdrugswerecollectedfromtheliterature.Quantitative toxicity-toxicityrelationship(QTTR)regressioncorrelationsofhumanandrodentlethaldoseswere poorforbothratandmouseoralandintraperitoneallethaldoses,butbothratandmouseintravenous LD50valuescorrelatedverywellwithhumanlethaldoses(r2=0.823and0.756,respectively).Ratand mouseintravenousLD50valuespredictedfromcommercialsoftwarealsocorrelatedreasonablywell withhumanlethaldoses(r2=0.631and0.678,respectively).Thismeansthatitshouldbepossible .tousethesecorrelationstopredictthehumanlethaldosesofnewpsychoactivedrugs Keywords Correlation, Human Lethal Dose, Prediction, Psychoactive Drugs, Rodent LD50 INTRoDUCTIoN Arecentcrimesurvey(CrimeSurveyforEnglandandWales,2016/17)revealedthat19.2%ofadults aged16to24hadtakenanillicitdruginthepastyear.AccordingtotheOfficeforNationalStatistics OfficeforNationalStatistics),deathsrelatedtodrugpoisoninginEnglandandWalesareincreasing) yearonyear,from2597in2012to3756in2017,anincreaseof44.6%.Hencethereisaneedforthe determinationoflethaltoxicity,basedusuallyonanimalexperiments,forbothmedicinesanddrugs .ofabuseinordertoobtainanestimationofsafetyandtoxicityinhumans Itisacknowledged(Gable,1993)thatthedeterminationofthehumanlethaldose(HLD)ofa psychoactivesubstanceisverydifficultforanumberofreasons,forexamplewhetherthesubstance ,istakenonitsownortogetherwithothersubstances,whetherthepersonisaneworhabitualuser whetherthepersonisaloneorinthecompanyofothers,andbecauseofthesometimesmarked ”interpersonalvariabilityofratesofmetabolism.Gable(1993)statedthat‘the“best-guesslethaldose foranaverageadulthumanwhohasnotdevelopedtolerancetothesubstanceisprobablytheLD50 DOI: 10.4018/IJQSPR.2019040101  .Copyright©2019,IGIGlobal.CopyingordistributinginprintorelectronicformswithoutwrittenpermissionofIGIGlobalisprohibited  1 International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019 extrapolatedfromabroadrangeoflaboratoryanimalstudiesthatfallswithintherangeoflethality .’citedinclinicalorforensicreports TheanimalLD50testwasdevelopedbyTrevan(1927)forthebiological standardization of drugs.LikeHLDvalues,itcannotbeconsideredasabiologicalconstant,forithasbeenpointed ,out(Zbinden&Flury-Roversi,1981)thatitcanvarywithanimalspecies,age,sex,weight,health geneticvariability,diet,methodofadministration,timeofassessmentafteradministration,ambient .temperature,housingconditions(e.g.isolatedoraggregated),timeofday/nightandtimeofyear ItisthereforenotsurprisingthatcorrelationsbetweenanimalLD50andhumantoxicityvaluesare ,generallypoor(Abbott,2005),althoughafewpublicationshavereportedmodestresults.Forexample Hoffmannetal.(2010)foundthathumanacutelethaldosesof30chemicalscorrelatedwithratoral 2 LD50values(coefficientofdetermination(r )=0.571);Ekwalletal.(1998)foundthathumanacute lethaldosesof50chemicals(includingafewpsychoactivedrugs)correlatedreasonablywellwith 2 ratandmouseoralLD50values(r =0.607and0.653respectively);Joveretal.(1992)reported correlationsbetweenHLDsof10chemicalswithratandmouseoralLD50values(predictionerrors 1.04and0.68logunitrespectively).Gable(2004)reportedmedianHLDandrangevaluesfor20 commonlyabusedpsychoactivesubstances;forexample,hegavethemedianHLDformethadone as100mg,andthelethalrangeas20–400mg.Hedidnot,however,examinepossiblecorrelations .betweenhumanandanimallethaldoses ByfarthemostwidelyusedanimalsinLD50testingarerodents,especiallyratsandmice.Itwas thereforedecidedtoexaminecorrelationsbetweenHLDsand(followingthesuggestionofGable arangeofratandmouseLD50values,withtheaimofobtainingoneormorevalidanimal((1993) modelsofhumanlethalityofpsychoactivedrugs.Suchmodelscouldthenbeusedtopredictthe humanlethalityofnew‘designer’drugsastheybecomeavailable.TheuseofmeanLD50valuesin thepresentworkhopefullymeansthatmanyexperimentalerrorsandvariationsintheirmeasurement .werecancelledout Methods Data ,(HLDvaluesfor18commonlyabusedpsychoactivesubstancesweretakenlargelyfromGable(2004 whoreportedthemfor20suchsubstances.However,twoofthosesubstances(isobutylnitriteand nitrousoxide)aregaseous,withdifferentdosageunits,andsocouldnotbeincludedinthepresent study.WhereGablegaveonlyarangeofvaluestogetherwithanindicationthatthemedianvalue was‘>X’,avalueonlyslightlygreaterthanXwasused;forexample,formethamphetamineGable gavethemedianvalueas>150mg,andtherangeas140-1650mg,soavalueof200mgwas(2004) selectedastheHLD.Valueswereconvertedtomg/kgusingarepresentativehumanweightof68kg .(BritishNationalFormulary2017-2018) ,The18psychoactivedrugscomprisedexamplesofopioids,benzodiazepines,amphetamines ,barbiturates, dibenzylcycloheptenes, morphinans, diphenylpropylamines, tryptamines, alcohols ,carboxylic acids, phenoxyphenylpropylamines, diphenylpropylamines, arylcyclohexylamines ,ergolinesanddibenzopyrans;theiractionsincludeddepressant,antidepressant,stimulant,hypnotic sedative,antitussive,hallucinogenic,anestheticandanalgesicactivities.Thisdemonstratesthevery .wideapplicabilitydomainofthedrugsusedinthiswork The physicochemical applicability domain covered a logarithmic octanol-water partition coefficient(logP)rangeof–0.70to7.68,apKa(base)rangeof2.2to10.3,apKa(acid)rangeof1.0 to9.6,andalogarithmicaqueoussolubility(logS,withSinmmol/L)of–5.49to0.79,aswellas .ethanolwhichhasinfinitesolubilityinwater Awide-rangingliteraturesearchwasperformedtofindratandmouseLD50valuesobtained viaoral,intraperitoneal,sub-cutaneousandintravenousadministration,andarithmeticmeanLD50 ,.valueswerecalculated, as has been done in previous studies (see, for example, Clothier et al Hoffmannetal.,2010).Ofthe144endpoints,foronly28(mostlyinvolvingsubcutaneous;1987 2 International Journal of Quantitative Structure-Property Relationships Volume 4 • Issue 2 • April-June 2019 administration)couldnoLD50valuesbefound.Table1givestheHLDvaluesandthemeanratand mouseLD50values.Whereavaluewasreportedforthesaltofadrug,thevaluewascorrectedtothat forthecorrespondingfreeacidorbaseusingtheratioofmolecularweights.Caraietal.(2004)have commentedthatsuchaproceduremaynotgivethecorrectvalueforthefreeacidorbase;usingthe exampleofthesodiumsaltofγ-hydroxybutyricacidtheypointedoutthatthesodiumioncouldhave contributedtotheobservedmortalitybychangingtheelectrolytichomeostasis.However,therewas nowaybywhichsuchsalteffectscouldbeallowedforindatacollectedfromtheliterature.Tables 1and2ofSupplementaryInformationgiveallthevaluesfound,andtheirsources;wheremorethan .onesourcegavethesamenumericalLD50value,onlyonesourceislisted ItshouldbenotedthatduringtheliteraturesearchnumerouserrorsinthereportingofLD50values cametolight.OneofthecommonestwasnotstatingwhetherornotanLD50valueforasalthadbeen correctedtothatofthefreeacidorbase;anothercommonerrorwasthemisreportingofsomeone else’spublishedvalue(s).Othersconcernedomissionoftherouteofadministration,thestrain,sex and/orageoftheanimalsused,thetimeafteradministrationatwhichdeathswerecounted,whether ornotanimalswerehousedinisolation,andtimeofdayortimeofyearwhentheexperimentswere performed.AnyorallofthesefactorscansignificantlyalterthemeasuredLD50valueofthecompound underinvestigation.TheuseofmeanLD50valuesinthepresentworkshouldcancelouttheeffects .ofsuchvariables,tosomeextentatleast Modeling .(MoleculardescriptorswerecalculatedfromMOEsoftware(MolecularOperatingEnvironment Quantitativetoxicity-toxicityrelationships(QTTRs)wereobtainedusingMinitabstatisticalsoftware v.18.1(Minitab)togeneratelinearregressionequations.FormodelingpurposesHLDandrodent ,LD50valuesinmg/kgunitswerefirstlyconvertedtommol/kgunits(Deardenetal.,2009).Next .thereciprocalsofthevaluesweretaken,simplysothatahighernumbermeansahighertoxicity Finally,thebase-10logarithmsofthevaluesweretaken,becauseLD50valuescanrangeoverseveral
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