Monit oring of 29 weight loss compounds in foods and dietary supplements by LC-M SMS

Monit oring of 29 weight loss compounds in foods and dietary supplements by LC-M S/MS

FoodAdditives&Contaminants:PartA,2014

Vol.31,No.5,777–783,/10.1080/19440049.2014.888497

Monitoringof29weightlosscompoundsinfoodsanddietarysupplementsbyLC-MS/MS

HyungJooKim,JiHyunLee,HyoungJoonPark,So-HyunCho,SooyeulChoandWooSeongKim*

AdvancedAnalysisTeam,ToxicologicalEvaluationandResearchDepartment,NationalInstituteofFoodandDrugSafetyEvaluation,MinistryofFoodandDrugSafety,Cheongwon-gun,Chungcheongbuk-do,Korea(Received23October2013;accepted24January2014)

Becauseoftherapidgrowthindietarysupplementavailabilityandpublicconcernforweightcontrol,theinvestigationoffoodsandvariousdietarysupplementsillegallyadulteratedwithweightlosscompoundshasbecomeincreasinglyimportant.Atotalof29weightlosscompounds,includingsennoside,sibutramine,ephedrineandtheiranalogues,foundtobeadulteratedinfoodsanddietarysupplementsweresimultaneouslyexaminedbyLC-MS/MS.The188sampleswerecollectedbetween2009and2012inSouthKorea,andmethodvalidationwasperformedtodeterminetheadulterantstotheweightlosscompounds.LODs,LOQsandlinearityrangedfrom0.03to7.5ngml 1,from0.08to30.00ngml 1,andfrom0.990to0.999,respectively.Theresultsshowedthatnineweightlosscompounds,namelybisacodyl,desmethylsibu-tramine,didesmethylsibutramine,ephedrine, uoxetine,pseudoephedrine,sennosideA,sennosideBandsibutramine,weredetectedin62ofallcollectedsamplesandwerefoundinorderoffrequencyasfollows:sibutramine,25.7%;sennosideA,22.9%;sennosideB,20.0%; uoxetine,8.6%;desmethylsibutramine,7.1%;bisacodyl,ephedrine,andpseudoephedrine,4.3%;anddidesmethylsibutramine,2.9%.Sibutramine,whichwasthemostfrequentlyfoundadulterant,rangedinlevelsfrom0.03to132.40mgg 1(2010),from0.88to76.2mgg 1(2011),andfrom0.07to0.24mgg 1(2012).Althoughtheconcentrationsofmostcompoundsrangedwidely,somecompoundssuchasbisacodyland uoxetinewerefoundathighconcentrationsinseveralsamples.

Keywords:weightlosscompound;obesity;dietarysupplements;LC-MS/MS

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Introduction

Obesitycanbede nedasachronicdiseasethatincludesdiabetes,cancerandcardiovasculardisease;theincidenceofobesityhasbeenincreasinginrecentyears(Sucaretal.2002;Ponnuruetal.2012;Lietal.2013).Thecausesofobesityarewidelyknowntoincludeexcessivecaloricintake,decreasedphysicalexerciseandirregulareatinghabits.Althoughdietingandphysicalactivitiesaretheuniversalsolutionstoovercomingobesity,thesearenotalwayseasytoachieve,andmanypatients ndthattakinganti-obesitydrugsismoreeffective(Jainetal.2006;Ariburnuetal.2012).Variousfoodsanddietarysupple-mentsarepreferablealternativestosyntheticanti-obesity,asevidencedbyalargeincreaseintheconsumptionofdietarysupplements(DeCarvalhoetal.2011).However,theuseofvariousweightlosssupplementssuchashealthfoodproducts,dietarysupplementsandherbalproductsisgainingworldwideacceptanceforhealthyliving.Becauseitisnearlyimpossibletoachieverapidshort-termeffectsfromdietarysupplements,someweightlosssupplementsareillegallyadulteratedwithanti-obesitydrugssuchassibutramine,sennosidesandephedrinetoimprovetheef cacyofweightloss(Kimetal.2009).Therefore,quantitativemonitoringofpharmaceuticalagentspresentinweightlosssupplementsisneeded(Leeetal.2013).

Methodsthathavepreviouslybeenusedtoanalyseweightlosscompoundsinvariousproductsincludeliquidchromatography-diodearraydetection(LC-UV),LC-MS/MS,GC-MS/MS,ionmobilityspectrometry,diffusion-orderedspectroscopy1Hnuclearmagneticresonance(DOSY1H-NMR),andX-raypowderdiffraction.Kimetal.(2009)andAriburnuetal.(2012)determinedweightlosscompoundsindietarysupplementsbyLC-UV.Ephedrine,fen uramine, uoxetineandsibutramineweresimultaneouslyassessedasawaytodevelopasimpler,moreaccurateandreliablemethodforanalysisofcom-pounds(Kimetal.2009).AnotherstudycomparedtheadvantagesbetweenHPLCandhigh-performancethin-layerchromatography(HPTLC)byanalysingsibutramine(Ariburnuetal.2012).Additionally,sevenadulterants,includingephedrineanalogues,weresimultaneouslydeter-minedbygaschromatography-electronionisation-tandemmassspectrometry(GC-EI-MS/MS)(Lietal.2012).Dunnetal.(2011,2012)surveyed11weightlosscompoundsbyionmobilityspectrometry,amoreuser-friendlymethodforthosewithlimitedchemistryexperience(Dunnetal.2012).Forafastmethodthatdoesnotdestroysamples,X-raypowderdiffractometrywasemployedtoscreenthreesibu-traminemetabolitesinherbaldietarysupplements(Stypulkowskaetal.2011).Vaysseetal.(2010)described

*Correspondingauthor.Email:kwsh1964@korea.kr

TheauthorsHyungJooKimandJiHyunLeecontributedequallytothewritingofthispaper.

©2014Taylor&Francis

Monit oring of 29 weight loss compounds in foods and dietary supplements by LC-M S/MS

778H.J.Kimetal.

unequivocalidenti cationofadulterantsinherbaldietarysupplementsusingDOSY1H-NMR.Shietal.(2011),Songetal.(2013),Lietal.(2010,2013),Ponnuruetal.(2012),Huangetal.(2008)andDeCarvalhoetal.(2011)developedmorerapidandaccurateLC-MS/MS-basedmeth-odsofanalysisfordeterminingthecomponentsofweightlosscompounds,includingsibutramineanditsanalogues,indietarysupplementsorhumanplasma.Althoughmanymethodsusingvariousanalyticalinstrumentshavebeentested,manypreviousstudiesofadulterationofsamplesbyweightlosscompoundshaveappliedchromatographicmeth-odstoquantifyandidentifythecontaminants.HPLCequippedwithESI-MS/MSisawell-establishedandwide-spreadtechniquefortheanalysisofvariouspharmaceuticalcomponentsillegallyusedtoadulteratefoodproducts.Moreover,therearecurrentlynoanalyticalmethodsreportedforthesimultaneousdeterminationof29weightlosscom-poundsfoundinfoodsanddietarysupplements.

Investigatingfoodsandvariousdietarysupplementsilleg-allyadulteratedwithanti-obesitydrugsisofgreaterimpor-tancetodaythaneverbeforebecauseoftherapidgrowthofthedietarysupplementmarket(Wooetal.2012).Therefore,inthisstudyreportedfoodsanddietarysupplementsthatweresuspectedofcausingside-effectswerecollectedovertheperiodfrom2009to2012inSouthKorea.Thesuspectsam-ples,illegallyadulteratedwith29anti-obesitycompounds,includingsibutramine,ephedrineandtheiranalogues,weresimultaneouslyexaminedbyLC-MS/MS.MaterialsandmethodsChemicals

Weightlosscompoundssuchasatenolol,bisacodyl,bupropion,caffeine,captopril,desmethylsibutramine,didesmethylsibutramine,diethylpropion,ephedrine,fen- uramine, uoxetine,levothyroxine,liothyronine,mazin-dol,moda nil,orlistat,paroxetine,phendimetrazine,phenobarbital,phenolphthalein,phentermine,phenytoin,propranolol,pseudoephedrine,sennosideA,sennosideB,sertraline,sibutramineandtheophyllinewerepurchasedfromUSP(Rockville,MD,USA).Acetonitrileandmetha-nolwereLC-MSgradeandHPLCgradeandpurchasedfromHoneywellBurdick&Jackson(Morristown,NJ,USA)andMerck(Darmstadt,Germany),respectively.FormicacidforthebuffersolutionwasobtainedfromSigma-Aldrich(St.Louis,MO,USA).Puri edwaterwaspreparedusingaMilliporeMilli-Qapparatus(Millipore,Billerica,MA,USA).Allsamplesandstan-dardsweresonicatedand lteredthrougha0.22-μmMilliporemembranebeforeinjection.Samples

Between2009and2012,122suspectfoodsand61dietarysupplementsadulteratedwithundeclaredpharmaceutical

ingredients,suchasweightlosscompounds,wereobtainedfromSouthKoreanmarkets.AllsampleswerestoredatRTuntilanalysis.

Preparationofstandardsandsamples

Eachofthe29standards was1dissolvedinmethanoltoaconcentrationof1mgmlforstocksolutionsandstoredrefrigeratedat4°C.Allstocksolutionswerecombinedforsimultaneousanalysisanddilutedto50,90,130,170,210and250ngml 1forcalibrationcurves.Approximately1gofsamplewasplacedintoa50-mlvolumetric ask,dilutedwithmethanolandthensonicatedfor30min.Alldilutedstockandsamplesolutionswere lteredthrougha0.22-μmMilliporemembrane lter.Eachsamplewasexaminedintriplicate.

LC-MS/MSconditions

AWatersAcquityUltraPerformanceLiquidChromatographicsystem(UPLC;Waters,Milford,MA,USA)equippedwithXevoTQ(Waters)wasusedforquanti cationofanti-obesitycompoundsinsamplesolutions.UPLCwasper-formedusingaBEHC18column(2.1ID×100mmlength,1.8μmparticlesize)andanovensetto30°C.ThemobilephasewascomposedofsolventsA(0.1%formicacidin5%acetonitrile)andB(0.1%formicacidin95%acetonitrile)forgradientuse.Thegradientprogrammewasasfollows:0–1min,5%B;1–5min,100%B;5–8min,100%B;8–8.1min,5%B;and8.1–10min,5%Btoequilibratefornextinjection(totalruntimewas10min).Thesolvent owratewas0.25mlmin–1,andtheinjectionvolumewas2μl.TheMSsystemwasusedinelectrosprayionisationmode.Desolvationgas owsandtemperaturesofpositiveandnegativeionmodewere550lh 1and300°Cand648lh 1and445°C,respec-tively.Thecapillaryvoltage–1was3.0kVandthecollisiongas owwas0.25mlminforoptimalanalyticalconditions.Methodvalidation

ValidationoftheLC-MS/MSanalyticalmethodwasper-formedforlinearity,LODandLOQ.Linearitywasdeter-minedforthestandardsolutionoverarangeof50–250ngml 1,asmentionedabove.LODsandLOQsweremarkedwhenthesignal-to-noise(S/N)ratioexceededvaluesof3and10,respectively.Standardsolu-tionswerespikedintoeachliquidandsolidsample(1g)tocalculatetherecovery.

Resultsanddiscussion

Inordertoquantifyrapidlyandsensitivelytheanti-obesitydrugsinadulteratedfoodsanddietarysupplements,LC-MS/MSusingESIinpositiveandnegativeion

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Monit oring of 29 weight loss compounds in foods and dietary supplements by LC-M S/MS

FoodAdditives&Contaminants:PartA

poundAtenololBisacodylBupropionCaffeineCaptopril

Desmethylsibutramine

Ionmode

++++++++++++++++++–+++++––+++

Precursorion267.15362.16240.09195.08218.09266.17252.16206.00166.15232.13310.13777.65651.75285.09296.08496.36330.14192.14231.05319.13150.14253.06260.15166.12861.20861.20306.08280.20181.08

Conevoltage(V)

3035223018201535202518353035302524352532162928185555202032

Production190.08145.10184.01226.02166.00184.02138.01110.0070.0274.96116.05179.03153.00139.00139.00153.01179.03105.00133.00148.03117.02115.01159.00187.02109.0044.01148.08731.65478.80605.80478.85130.1044.00128.95319.25160.05123.00150.96192.12148.05115.00187.95197.08225.00133.0491.0077.01182.0874.00116.04148.05117.01115.01386.00224.00386.00224.00158.90275.02138.90124.90124.0096.00

779

Collisionenergy(V)

25253030181325202018121513151010102010102020201540108285023353525121313221818202812302510184315201810182540604065301330352022

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DidesmethylsibutramineDiethylpropionEphedrineFen uramineFluoxetineLevothyroxineLiothyronineMazindolModa nilOrlistatParoxetinePhendimetrazinePhenobarbitalPhenolphtaleinPhenterminePhenytoinPropranololPseudoephedrineSennosideASennosideBSertralineSibutramineTheophylline

Monit oring of 29 weight loss compounds in foods and dietary supplements by LC-M S/MS

780H.J.Kimetal.

showedgoodlinearity,withcorrelationcoef cientsovertherangeof0.990–0.999,asshowninTable2.TheLODsweredeterminedoverawiderange,from0.03to7.50ngml 1,atanS/Nof3.TheLOQswerecalculatedfromanS/Nof10,andtheexaminedLOQsforeachweightlosscompoundrangedfrom0.08ngml 1forphenobarbitalto30.00ngml 1forsennosideA.LODsandLOQsofsennosidesAandBwererelativelyhigherthanthoseoftheothercompounds.Therecoverywascarriedoutbystandardadditionmethodandde nedastheratioofthemeasuredvaluetotheknownconcentration.Atotalof1gofmixedstandardsolutionofweightlosscompoundswasspikedintoeachsample.Theaveragerecoveriesofthosespikedsampleswereintherangeof80–120%(datanotshown).OurmethodvalidationindicatedthattheLC-MS/MSanalysismethodissuitableforthedeterminationof29weightlosscompounds,includingsibutramine,sennosideandephedrine,infoodanddietarysupplementsamples.

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modeswasusedtocon rmthemolecularions.Toinves-tigatetheproductspectraofeachanalyte,previouslypre-paredstandardsolutionsweredirectlyinfusedintothesyringepump.TheoptimisedMRMtransitionparametersofLC-MS/MSfordetectingthestandardsareshowninTable1.OnlysennosideA,sennosideBandphenobarbitalshoweddeprotonatedmolecularions,as[M–H]–,whereas26othercompoundsexistedas[M+H]+.Foreachcompoundatleasttwoproductionsfragmentedfromprecursorionswereselectedasqualitativeions,andthemostabundantproductionswerechosenasthequanti ca-tionion.

Analyticalqualityassurancewascarriedoutbyestab-lishinglinearity,LOD,LOQandrecovery,referringtotheICH(Q2A,Q2B)andUSP(Chapter1225:ValidationofCompendiaMethods).Allweightlosscompoundsweremixedanddilutedto50,90,130,170,210and250ngml 1toobtaincalibrationcurves.Eachcompound

Table2.

Correlationcoef cients(R2),LODandLOQof29weightlosscompoundsperformedbythestandardadditionmethod.

R20.9910.9920.9990.9910.9960.9950.9970.9990.9970.9920.9900.9920.9940.9920.991

LOD(ngml 1)

0.250.250.752.500.250.080.250.030.500.080.251.000.303.001.00

LOQ(ngml 1)

0.750.753.008.000.750.250.750.100.750.130.753.001.007.503.00

CompoundOrlistatParoxetine

PhendimetrazinePhenobarbitalPhenolphtaleinPhenterminePhenytoinPropranolol

PseudoephedrineSennosideASennosideBSertralineSibutramineTheophylline

R20.9980.9980.9960.9930.9960.9950.9910.9960.9950.9910.9910.9940.9950.995

LOD(ngml 1)

0.050.500.750.030.502.501.250.251.257.503.000.100.051.00

LOQ(ngml 1)

0.130.755.000.080.758.005.000.502.5030.007.500.300.753.00

Compound

AtenololBisacodylBupropionCaffeineCaptopril

DesmethylsibutramineDidesmethylsibutramineDiethylpropionEphedrineFen uramineFluoxetineLevothyroxineLiothyronineMazindolModa nil

Table3.Detectednumbersof29weightlosscompoundsadulteratedinfoods(n=127)anddietarysupplements(n=61)duringtheperiodof2009through2012inSouthKorea.AdulteratedcompoundBisacodyl

DesmethylsibutramineDidesmethylsibutramineEphedrineFluoxetine

PseudoephedrineSennosideASennosideBSibutramine

NumberofpositivesamplesNumberofnegativesamplesNumberofsamplesexamined

2009n.d.n.d.n.d.n.d.n.d.n.d.64111324

2010n.d.1n.d.n.d.n.d.n.d.104215374

201132n.d.363428113344

2012n.d.22n.d.n.d.n.d.442192746

Total35236316141862126188

Percentageratio

4.297.142.864.298.574.2922.8620.0025.71

Note:n.d.,Notdetected;Total,sumofeachrow;percentageratiowascalculatedbydividingthenumberofdetectedsamplesofeachcompoundbythetotalsumofthedetectedsamples.

Monit oring of 29 weight loss compounds in foods and dietary supplements by LC-M S/MS

FoodAdditives&Contaminants:PartA

Onlynineweightlosscompounds,bisacodyl,des-methylsibutramine,didesmethylsibutramine,ephedrine, uoxetine,pseudoephedrine,sennosideA,sennosideBandsibutramine,ofatotalof29compoundsweredetectedinthefoodanddietarysupplementsamples(n=188)collectedover4yearsinSouthKorea(Table3).TheMRMchromato-gramsoftheadulteratingcompoundsareshowninFigure1.Desmethylsibutramine,didesmethylsibutramineandpseu-doephedrineareanaloguesofsibutramineand

ephedrine.

Table4.

781

Differenttypesofsamplesfoundtobeadulterated.

Numberofsamples

2015138662

Percentageratio

32.324.221.012.99.6100

TypeofsamplePowderTabletGranuleCapsuleLiquidTotal

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Figure1.MRMchromatogramsofnineweightlosscompoundsfoundinadulteratedsamples.

Monit oring of 29 weight loss compounds in foods and dietary supplements by LC-M S/MS

782H.J.Kimetal.

Table5.Concentrationranges(mgg 1)oftheweightlosscompoundsmeasuredinfoodsanddietarysupplementsduring2009–12inSouthKorea.AdulteratedcompoundBisacodyl

DesmethylsibutramineDidesmethylsibutramineEphedrineFluoxetine

PseudoephedrineSennosideASennosideBSibutramine

2009n.d.n.d.n.d.n.d.n.d.n.d.

0.41–6.40n.d.

201025.40–45.100.55–43.40n.d.n.d.

96.10–201.10n.d.

8.04–28.910.03–132.40

2011199.70n.d.n.d.

7.07–8.510.01–176.603.67–4.172.26–2.752.74–3.270.88–76.2

2012n.d.

0.02–0.075.01–12.79n.d.n.d.n.d.

0.34–0.520.23–0.350.07–0.24

Note:n.d.,Notdetected;sennosidesAandBwerenotdistinguishedin2009and2010.

Sibutraminewasdetectedforallofthe4yearsexamined,butdesmethylsibutramineanddidesmethylsibutraminewerenotdetectedinsamplestakenin2009and2009–10,respec-tively.Thefrequencyofdetectionoftheanaloguesinadult-eratedsamplesincreasedthenextyear,althoughtheincreasesweresmall.Thepercentageratiosofdetectedsam-plesofeachcompoundwerefoundinthefollowingorderoffrequency:sibutramine,25.71%;sennosideA,22.86%;sen-nosideB,20.00%; uoxetine,8.57%;desmethylsibutramine,7.14%;bisacodyl,ephedrine,andpseudoephedrine,4.29%;anddidesmethylsibutramine,2.86%.Inaddition,approxi-matelyone-thirdofthesampleswereadulteratedwithweightlosscompoundsoverthe4-yearperiod,as62ofthe188examinedsampleswerepositive(Table3).TheadulteratedsamplesareindicatedinTable4.Weightlosscompoundswereillegallyadulteratedinthesamplesofvarioustypes.Theconcentrationrangesoftheweightlosscompoundsmeasuredinsamplesovertheperiod2009–12areindicatedinTable5.Theconcentrationsofsibutramine,themostfrequentadulterant,rangedwidelyfrom0.03to132.40mgg 1(2010),from0.88to76.2mgg 1(2011),andfrom0.07to0.24mgg 1(2012).Theamountofsenno-sideArangedfrom0.41to6.40mgg 1(2009),from8.04to28.91mgg 1(2010),from2.26to2.75mgg 1(2011),andfrom0.34to0.52mgg 1(2012).Thelevelsofsibutramine,bisacodyland uoxetinewereextremelyhighinseveralsamples.Inapreviousstudy,Shietal.(2011)alsoreportedexceedinglyhighsibutramineconcentrationsintwoof10samples.Thisstudyindicatedthatsibutramineposesathreattohumanhealthifregularlyingested.

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respectively,andthecorrelationcoef cientsofthelinearregressionrangedfrom0.990to0.999.Methodvalidationwassuf cientintermsofLOD,LOQ,ingthevalidatedLC-MS/MSmethod,wecon rmedthatinatotalof188samples,62wereillegallyadulteratedwithnineweightlosscompounds.Althoughthelevelsofthecontaminantswouldnotposeadirecthealththreat,theycanbearisktohumanhealthifregularlyingested.Therefore,furthermonitoring-relatedresearchandinvesti-gationofnewcompoundsshouldbeperformedtocontrolillegaladulterationoffoodsanddietarysupplements.Funding

TheauthorsthanktheMinistryofFoodandDrugSafety(MFDS)inKoreafor nancialsupport.

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