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Screening of 300 Drugs in Blood Utilizing Second Generation

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Screening of 300 Drugs in Blood Utilizing Second Generation Forensic Screening of 300 Drugs in Blood Utilizing Exactive Plus High-Resolution Accurate Mass Spectrometer and ExactFinder Software Kristine Van Natta, Marta Kozak, Xiang He Forensic Toxicology use Only Drugs analyzed Compound Compound Compound Atazanavir Efavirenz Pyrilamine Chlorpropamide Haloperidol Tolbutamide 1-(3-Chlorophenyl)piperazine Des(2-hydroxyethyl)opipramol Pentazocine Atenolol EMDP Quinidine Chlorprothixene Hydrocodone Tramadol 10-hydroxycarbazepine Desalkylflurazepam Perimetazine Atropine Ephedrine Quinine Cilazapril Hydromorphone Trazodone 5-(p-Methylphenyl)-5-phenylhydantoin Desipramine Phenacetin Benperidol Escitalopram Quinupramine Cinchonine Hydroquinine Triazolam 6-Acetylcodeine Desmethylcitalopram Phenazone Benzoylecgonine Esmolol Ranitidine Cinnarizine Hydroxychloroquine Trifluoperazine Bepridil Estazolam Reserpine 6-Monoacetylmorphine Desmethylcitalopram Phencyclidine Cisapride HydroxyItraconazole Trifluperidol Betaxolol Ethyl Loflazepate Risperidone 7(2,3dihydroxypropyl)Theophylline Desmethylclozapine Phenylbutazone Clenbuterol Hydroxyzine Triflupromazine Bezafibrate Ethylamphetamine Ritonavir 7-Aminoclonazepam Desmethyldoxepin Pholcodine Clobazam Ibogaine Trihexyphenidyl Biperiden Etifoxine Ropivacaine 7-Aminoflunitrazepam Desmethylmirtazapine Pimozide Clofibrate Imatinib Trimeprazine Bisoprolol Etodolac Rufinamide 9-hydroxy-risperidone Desmethylnefopam Pindolol Clomethiazole Imipramine Trimetazidine Bromazepam Felbamate Secobarbital Clomipramine Indalpine Trimethoprim Acepromazine Desmethyltramadol Pipamperone Brompheniramine Fenfluramine Selegiline Clonazepam Indinavir Trimipramine Aceprometazine Dexamethasone Pipotiazine Bufotenine Fenofibrate Sertraline Clonidine Indometacin Tropatepine Alfentanyl Dextromethorphan Posaconazole Bupropion Finasteride Sotalol Clotiazepam Iproniazid Urapidil Alfuzosine Dextropropoxyphene Pramipexole Buspirone Flecainide Strychnine Clozapine Isocarboxazide Valpromide Butorphanol Fluconazole Sufentanil Alimemazine Dextrorphan Prazepam Clozapine N-oxide Itraconazole Venlafaxine Cafeine Flunarizine Sultopride Alprazolam Diazepam Prednisone Cocaethylene Ketamine Verapamil Cannabidiol Flunitrazepam Temazepam Amidopyrine Dibenzepine Primaquine Cocaine Ketoconazole Viloxazine Carbamazepine Flunixin Terbinafine Amiodarone Diltiazem Primidone Codeine Ketoprofen Vincristine Carbamazepine epoxyde Fluoxetine Terfenadine Amisulpride Dimetotiazine Prochlorperazine Colchicine Ketotifen Voriconazole Carbutamide Fluoxymesterone Tetrazepam Amitriptyline Diphenhydramine Procyclidine Cotinine Lacidipine Yohimbine Carpipramine Flupentixol THCA Coumatetralyl Lacosamide Zimelidine Amlodipine Dipyridamole Proguanil Celiprolol Fluphenazine Thioproperazine Cyamemazine Lamotrigine Ziprasidone Amoxapine Disopyramide Promazine Cetirizine Flurazepam Thioridazine Cyclobenzaprine LAMPA Zolpidem Amprenavir Domperidone Promethazine Chlordiazepoxide Fluvoxamine Thioridazine sulfone Cyclophosphamide Levomepromazine Zonisamide Anhydroecgonine methyl ester Dosulepin Prometryn Chlormezanone Galantamine Tianeptine Cyproheptadine Levorphanol Zopiclone Antipyrine Doxepine Propericiazine Chloroquine Glafenine Tiapride Dapsone Lidocaine Zuclopenthixol Apocodeine Droperidol Propizepine Chlorpheniramine Glibornuride Timolol Darunavir Linezolid Aprindine Dropopizine Propranolol Chlorproethazine Gliclazide Tinidazole Deacetyl Diltiazem Lopinavir Astemizole Duloxetine Protriptyline Chlorpromazine Glipizide Tofisopam Demexiptiline Loprazolam Forensic Toxicology use Only 2 Study design and data analysis • LOD determination • aliquots of whole blood were spiked with sets compound at 5, 10, 20, 50, and 100 ng/mL • Matrix effects determination • Compare signals in samples spiked in water vs blood. • Data Analysis • Chromatograms are reconstructed with a mass tolerance of 5 ppm • Compounds identified based on exact mass and retention time • Confirmation with fragments and isotopic pattern using ExactFinder™ software. Forensic Toxicology use Only 3 Sample Preparation Procedure 50 µL whole blood Add 5uL IS (Reserpine and Toludamide-d9) Add 150 µL of 40mM ZnSO4 in 66% methanol Place samples in a –20°C freezer for 20-30 minutes Centrifuge at 13,000 rpm for 10 min Inject 20 uL of supernatant Forensic Toxicology use Only 4 LC-MS/MS setup • Thermo Scientific Accela 600 pump with Accela™ open autosampler • Exactive Plus System • Mobile phases • 10 mM ammonium acetate with 0.1% ammonia in water (A) • methanol (B), and • acetonitrile:1-propanol:acetone (45:45:10) (C) • Gradient • HPLC column • Thermo Hypersil GOLD, 5 µm, 100 x 3 mm run under the • Divert valve • set to waste from 0 to 1 minutes, • to mass spectrometer from 1 minute to the end of the run. Forensic Toxicology use Only 5 Exactve Plus method • APCI source • Alternating positive and negative full-scan at 70,000 resolution • All-ion fragmentation (AIF) with fast polarity switching at 35,000 resolution Forensic Toxicology use Only 6 ExactFinder software - Database Forensic Toxicology use Only 7 ExactFinder software screening method Forensic Toxicology use Only 8 Example chromatogram at 5 ng/mL RT: 0.00 - 14.89 SM: 5B RT: 0.00 - 14.01 SM: 5B RT: 5.93 NL: 4.95E4 RT: 9.11 NL: 3.15E3 SN: 118 m/z= 249.0680-249.0704 F: SN: 54 m/z= 316.0064-316.0096 F: 100 FTMS + p APCI corona Full ms 100 FTMS + p APCI corona Full ms [120.00-1200.00] MS ICIS [120.00-1200.00] MS ICIS Dapsone 5ng-2 5ng-4 50 50 Bromazepam 0 0 RT: 12.32 NL: 3.15E4 RT: 10.16 NL: 7.92E3 SN: 621 m/z= 285.1406-285.1434 F: SN: 41 m/z= 300.0883-300.0913 F: 100 FTMS + p APCI corona Full ms 100 FTMS + p APCI corona Full ms [120.00-1200.00] MS 5ng-2 [120.00-1200.00] MS ICIS Promethazine 5ng-6 50 50 Chlordiazepoxide 0 0 RT: 12.69 NL: 2.08E4 RT: 11.63 NL: 3.52E5 SN: 56 m/z= 315.1607-315.1639 F: SN: 319 m/z= 609.2777-609.2837 F: 100 FTMS + p APCI corona Full ms 100 FTMS + p APCI corona Full ms [120.00-1200.00] MS ICIS [120.00-1200.00] MS ICIS Clomipramine 5ng-2 5ng-1 50 50 Reserpine-pos 0 0 RT: 6.96 NL: 3.76E3 RT: 11.64 NL: 7.11E3 SN: 21 m/z= 286.0728-286.0756 F: SN: 38 m/z= 607.2631-607.2691 F: 100 FTMS + p APCI corona Full ms 100 FTMS - p APCI corona Full ms [120.00-1200.00] MS ICIS [120.00-1200.00] MS ICIS 5ng-20 5ng-1 50 50 Reserpine-neg 7-Aminoclonazepam 0 0 RT: 12.53 NL: 3.52E4 RT: 7.32 NL: 2.98E6 SN: 86 m/z= 472.3186-472.3234 F: SN: 19667 m/z= 280.1662-280.1690 F: 100 FTMS + p APCI corona Full ms 100 FTMS + p APCI corona Full ms [120.00-1200.00] MS ICIS [120.00-1200.00] MS ICIS Terfenadine 5ng-2 5ng-1 50 50 Tolbutamide-D9-pos 0 0 RT: 7.35 NL: 1.39E6 RT: 7.30 NL: 2.29E5 SN: 944 m/z= 280.1682-280.1710 F: SN: 385 m/z= 278.1516-278.1544 F: 100 FTMS + p APCI corona Full ms 100 FTMS - p APCI corona Full ms [120.00-1200.00] MS ICIS [120.00-1200.00] MS ICIS 5ng-3 5ng-1 50 Doxepine 50 Tolbutamide-D9-neg 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Time (min) Time (min) Forensic Toxicology use Only 9 Ion suppression < 50% Hydrocodone shows no ion suppression Water Blood Forensic Toxicology use Only 10 ExactFinder software results review Forensic Toxicology use Only 11 LOD Compound LOD Compound LOD Compound LOD Compound LOD 1-(3-Chlorophenyl)piperazine 5 Des(2-hydroxyethyl)opipramol 5 Loratadine 5 Pentazocine 5 10-hydroxycarbazepine 10 Desalkylflurazepam 5 Lorazepam 5 Perimetazine 5 5-(p-Methylphenyl)-5-phenylhydantoin 20 Desipramine 5 Lormetazepam 5 Phenacetin 5 6-Acetylcodeine 10 Desmethylcitalopram 5 Loxapine 5 Phenazone 5 6-Monoacetylmorphine 5 Desmethylcitalopram 5 LSD 5 Phencyclidine 5 7(2,3dihydroxypropyl)Theophylline 5 Desmethylclozapine 50 Maprotiline 5 Phenylbutazone 10 7-Aminoclonazepam 5 Desmethyldoxepin 5 Maraviroc 5 Pholcodine 10 7-Aminoflunitrazepam 5 Desmethylmirtazapine 10 MBDB 10 Pimozide 5 9-hydroxy-risperidone 5 Desmethylnefopam 5 MDEA 10 Pindolol 5 Acepromazine 5 Desmethyltramadol 10 MDMA 10 Pipamperone 5 Aceprometazine 5 Dexamethasone 5 Mebutamate 20 Pipotiazine 5 Alfentanyl 5 Dextromethorphan 5 Medazepam 5 Posaconazole 5 Alfuzosine 5 Dextropropoxyphene 10 Medifoxamine 5 Pramipexole 5 Alimemazine 5 Dextrorphan 5 Mefloquine 5 Prazepam 5 Alprazolam 5 Diazepam 5 Melatonin 5 Prednisone 5 Amidopyrine 5 Dibenzepine 5 Mepivacaine 5 Primaquine 10 Amiodarone 10 Diltiazem 5 Meprobamate 20 Primidone 10 Amisulpride 5 Dimetotiazine 5 Mescaline 50 Prochlorperazine 5 Amitriptyline 5 Diphenhydramine 5 Mesoridazine 5 Procyclidine 5 Amlodipine 5 Dipyridamole 50 Metenolone 20 Proguanil 5 Amoxapine 5 Disopyramide 10 Methadone 5 Promazine 10 Amprenavir 5 Domperidone 5 Methamphetamine 10 Promethazine 5 Anhydroecgonine methyl ester 10 Dosulepin 5 Methandienone 50 Prometryn 5 Antipyrine 5 Doxepine 10 Methaqualone 5 Propericiazine 5 Apocodeine 5 Droperidol 20 Methotrimeprazine 5 Propizepine 5 Aprindine 5 Dropopizine 5 Methoxsalen 5 Propranolol 5 Astemizole 5 Duloxetine 10 Methoxyamphetamine 50 Protriptyline 5 Forensic Toxicology use Only 12 LOD cont… Atazanavir 5 Efavirenz 5 Methoxymethamphetamine 5 Pyrilamine 5 Atenolol 5 EMDP 5 Methylene Blue 100 Quinidine 5 Atropine 5 Ephedrine 50 Methylphenidate 10 Quinine 5 Benperidol 10 Escitalopram 5 Metobromuron 5 Quinupramine 5 Benzoylecgonine 5 Esmolol 5 Metoclopramide 5 Ranitidine 5 Bepridil 5 Estazolam 5 Metronidazole 5 Reserpine 5 Betaxolol 5 Ethyl Loflazepate 5 Mexiletine 10 Risperidone 5 Bezafibrate 20 Ethylamphetamine 5 Mianserine 5 Ritonavir 10 Biperiden 5 Etifoxine 5 Midazolam 5 Ropivacaine 5 Bisoprolol 5 Etodolac 10 Milnacipram 5 Rufinamide 5 Bromazepam 5 Felbamate 5 Molsidomine 5 Secobarbital 50 Brompheniramine 5 Fenfluramine 5 Morphine 10 Selegiline 50 Bufotenine 50 Fenofibrate
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