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A Complete Toxicology Screening Procedure for Drugs and Toxic Compounds in Urine and Plasma Using LC-MS/MS

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A Complete Toxicology Screening Procedure for Drugs and Toxic Compounds in Urine and Plasma Using LC-MS/MS Application Note: 449 A Complete Toxicology Screening Procedure for Drugs and Toxic Compounds in Urine and Plasma Using LC-MS/MS Marta Kozak, Taha Rezai, Thermo Fisher Scientific, San Jose, CA Introduction Key Words Toxicology laboratories commonly use automated Scan Event 1 Scan Event 7 + Full Scan MS – Full Scan MS • ToxSpec immunoassays, gas chromatography-mass spectrometry Analyzer (GC-MS) and high pressure liquid chromatography-diode array detector (HPLC-DAD) techniques to perform • ToxID Software toxicology screening analyses. None of these techniques • LXQ Linear Ion are able to identify all the drugs and toxic compounds Trap that are potentially present in a sample. Implementation of liquid chromatography-mass spectrometry (LC-MS) for • Clinical toxicology screening provides specific and sensitive Toxicology analysis of drugs and toxic substances. The benefits of the • General LC-MS/MS screening methodology include a simple Unknown sample preparation procedure, ease of adding new Screening compounds to the screening method and fewer limitations based on compound volatility and thermal stability. In Scan Event 2-6 Scan Event 8-9 addition, Thermo Scientific ToxID automated toxicology + MS/MS on parent list – MS/MS on parent list screening software is able to automatically generate both Summary and Long Reports, avoiding the need for Figure 1: MS scan events manual analysis of each sample chromatogram. This application note describes the use of the Thermo Scientific LXQ ion trap mass spectrometer equipped with an ESI source and HPLC for identification of unknown compounds in human urine and human plasma. Step 1: Extract analytes from urine or plasma with SPE procedure Goal To develop a complete LC-MS/MS screening methodology which includes a sample preparation method, LC-MS Step 2: Analyze the samples method, spectra library, and data processing and reporting with LC-MS/MS method software. Experimental Conditions Step 3: Automated library search and An MS/MS spectral library of 275 drugs and toxic reporting with software compounds was created. Sample preparation of spiked human urine or human plasma was carried out using a solid-phase extraction (SPE) cartridge for basic, neutral Figure 2: Step-by-step application workflow and acidic compounds. A 13-minute LC method implementing a Perfluorophenyl (PFP) column was developed. Samples were analyzed using electrospray Sample Preparation ionization (ESI) on an ion trap mass spectrometer in Samples (1 mL of urine or 0.5 mL of plasma) were spiked polarity switching scan dependent MS/MS experiments with 0.1 mL of an internal standard solution at a (see Figure 1), with retention time windows specified for concentration of 1 µg/mL (Chlorpromazine-D3, each listed parent mass. The method allows acquisition of Haloperidol-D4 and Prazepam-D5) and diluted with 2 mL MS2 spectra for co-eluting compounds and analysis of of 0.1 M phosphate buffer pH 6.0. The resulting mix was positively and negatively ionized compounds with a single extracted with an SPE (Thermo Scientific Hypersep Verify- run. Figure 2 shows the overall application workflow. CX 200 mg mixed mode cartridges) procedure prior to injection onto LC-MS. Chromatography MS Conditions HPLC separation was performed with a Thermo Scientific Accela pump using a Thermo Scientific Hypersil GOLD Instrument: LXQ ion trap mass spectrometer PFP column (50 x 2.1 mm; 5 µm particles). Flow rate was Ionization: ESI, Thermo Scientific Ion Max source set to 200 µL/min. The gradient is summarized in Table 1 Capillary temperature: 275 ˚C (solvent A = water/0.1% formic acid/10 mM ammonium Spray voltage: 5.0 kV formate, solvent B = acteonitrile/0.1% formic acid). Sheath gas: 30 Injection volume was 10 µL. Aux gas: 8 Data acquisition mode: Polarity switching scan dependent experiment Microscans: 1 Table 1. Thirteen-minute LC method WideBand Activation™: On Time (minutes) %A %B Stepped Normalized Collision Energy: 35% ± 10% 0955 0.5 95 5 5.5 5 95 8.5 5 95 Method Validation and Results: 8.6 5 95 The method was prequalified by processing and analyzing 13 95 5 urine samples spiked with 10 randomly selected compounds in concentrations of 10 ng/mL, 100 ng/mL and 1000 ng/mL. Table 2 lists the concentration at which each analyte in the toxicology screen for urine samples is identified. The presence of an analyte at 10, 100 or 1000 ng/mL implies that the limit of detection is likely below that value. Of the 275 compounds analyzed, 70% were detected at 10 ng/mL, 20% at 100 ng/mL, 8% at 1000 ng/mL and 2% were detected at a concentration above 1000 ng/mL. Table 2. Results for spiked urine samples in toxicology screen by LC-MS/MS LXQ – 13 min method Concentration Tested (ng/mL) Compound 10 100 1000 All barbiturates require an APCI source for detection. P=Drug present. N=Drug not present. 11-Hydroxy-delta-9-THC NN>1000 11-nor-9-carboxy-Delta-9-THC NNP 2-Bromo-Alpha-Ergocryptine P P P 2-Hydroxyethylflunitrazepam N PP 3-Hydroxystanozolol NN>1000 4-Hydroxynordiazepam N PP 6-Acetylcodeine P P P 6-Acetylmorphine (6-MAM) P P P 7-Amino-Clonazepam P P P 7-Amino-Flunitrozepam P P P Acebutolol P P P a-Hydroxy-Alprazolam P P P a-Hydroxy-Triazolam P P P Albuterol P P P alpha-Hydroxymidazolam N PP Alprazolam P P P Alprenolol P P P Aminorex N PP Amiodarone P P P Amitriptyline P P P Amlodipine NNP Amobarbital P P P Amoxapine P P P Amphetamine P P P Anhydroecgonine MethylEster N PP Antipyrine NN>1000 Apomorphine NN>1000 LXQ – 13 min method Concentration Tested (ng/mL) Compound 10 100 1000 Astemizole N PP Atenolol P P P Atropine N PP BDB N PP Benzocaine NNP Benzoylecgonine N PP Betaxolol P P P Bisacodyl P P P Bisoprolol P P P Bromazepam P P P Brompheniramine P P P Bupivocaine P P P Buprenorphine P P P Bupropion P P P Buspirone P P P Butalbital N PP Butorphanol P P P Cannabidiol NN>1000 Cannabinol NN>1000 Captopril NNP Carbamazepine P P P Carbinoxamine N PP Carisoprodol NNP Cathinone NNP Chlordiazepoxide P P P Chlorothiazide N PP Chlorpheniramine P P P Chlorpromazine P P P Chlorpromazine-D3 N PP Chlorprothixene NN>1000 Cinnarizine P P P cis-4-Methylaminorex N PP Cisapride N PP Citalopram P P P Clenbuterol P P P Clenbuterol N PP Clobazam N PP Clomipramine P P P Clonazepam P P P Clonidine P P P Clopidogrel P P P Clozapine P P P Cocaethylene P P P Cocaine P P P Codeine P P P Cyclobenzaprine P P P Delta9-THC N PP Desalkylflurazepam N PP Desipramine N PP Desmethyldoxepin P P P Dextromethorphan P P P Diazepam P P P Diflunisal P P P Digoxin NNP Dihydrocodeine P P P Dihydroergotamine P P P Diltiazem P P P Diphenhydramine P P P Dipyridamole NNP Disopyramide P P P Dothiepin N PP Doxepin P P P Doxylamine P P P Ecgonine-Methyl-Ester NNP EDDP P P P EMDP P P P Enalapril P P P Ephedrine N PP LXQ – 13 min method Concentration Tested (ng/mL) LXQ – 13 min method Compound 10 100 1000 Compound Ergotamine P P P Mianserin Estazolam N PP Miconazole Felcainide P P P Midazolam Fendiline P P P Mirtazapine Fenfluramine P P P Molsidomine Fentanyl P P P Morphine Fexofenadine P P P Morphine-3-b-glucuronide Flumethasone NNP Nalbuphine Flunitrazepam P P P Nalorphine Flunixin N PP Naloxone Fluoxetine P P P Naltrexone Fluoxymesterone N PP NAPA Fluphenazine P P P N-DemethylTrimipramine Flurazepam P P P N-Desmethyl-cis-tramadol Fluvoxamine P P P N-Desmethylflunitrazepam Furosemide N PP N-Desmethylselegiline Gabapentin NNP N-DesmthylClomipramine Gliclazide NNP N-Ethylamphetamine Glimepiride N PP Nicardipine Glipizide P P P Nicotine Glyburide P P P Nitrazepam Haloperidol P P P Nitrendipine Haloperidol-D4 N PP Nizatidine Heroin P P P Norbenzoylecgonine HMMA NN>1000 Norbuprenorphine Hydrochlorothiazide NNP Norclomipramine Hydrocodone P P P Norcocaethylene Hydromorphone P P P Norcocaine Hydroxyzine N PP Norcodeine Imipramine P P P Nordiazepam Indomethacin NN>1000 Nordoxepin Isradipine P P P Norethandrolone Ketamine P P P Norfentanyl Ketoconazole P P P Norfluoxetine Ketoprofen NN>1000 Norketamine Ketorolac NN>1000 NOR-LSD Labetolol N PP Normeperidine Lamotrigine P P P Normorphine LAMPA P P P Noroxycodone Lidocaine P P P Noroxymorphone Lometazepam N PP Norproproxyphene Loratadine P P P Nortriptyline Lorazepam P P P Noscapine LSD PPP OH-LSD Maprotiline P P P Ondansetron MBDB N PP Opipramol MDA PPP Oxazepam MDEA N PP Oxcarbazepine MDMA P P P Oxycodone Melatonin NN>1000 Oxymorphone Meperidine P P P Papaverine Mepivocaine N PP Paraxanthine Meprobamate N PP Paroxetine Mescaline P P P PCP Mesoridazine P P P Pentazocine Metaprolol P P P Pentobarbital Methadienone P P P Perphenazine Methadone P P P Pheniramine Methamphetamine P P P Phenobarbital Methaqualone NN>1000 Phenolphthalein Methcathinone NNP Phentermine Methenolone P P P Phenylbutazone Methohexital P P P Phenyltoloxamine Methoxyverapmil P P P Physostigmine Methylphenidate P P P Pindolol Metoclopramide P P P Piroxicam Metronidazole N PP PMA Mexiletine NN>1000 PMMA Concentration Tested (ng/mL) LXQ – 13 min method Concentration Tested (ng/mL) 10 100 1000 Compound 10 100 1000 PPP Prazepam-D5 N PP PPP Prazosin P P P PPP Prilocaine NNP PPP Procainamide N PP NN>1000 Promazine P P P N PP Promethazine N PP NN>1000 Prometryn N PP PPP Propafenone P P P PPP Propoxyphene P P P PPP Propranolol P P P PPP Protriptyline P P P PPP Psilocin N PP PPP Pyrilamine P P P NNP Quetiapine P P P N PP Quinidine P P P N PP Quinine N PP N PP Ranitidine NNP N PP Risperidone P P P PPP Scopolamine P P P PPP Secobarbital P P P NN>1000 Selegiline N PP PPP Sertraline P P P NNP Sotalol N PP NN>1000 Spironolactone N PP NN>1000 Stanozolol N PP PPP Telmisartan P P P PPP Temazepam P P P PPP Terfenadine P P P N PP Tetracine P P P PPP Thiamylal N PP PPP Thiopental P P P N PP Thioridazine P P P N PP Thiothixene P P P PPP Timolol P P P N PP Topiramate P P P PPP Trazodone P P P PPP Triazolam P P P NNP Trimethoprim P P P N PP Trimipramine P P P NN>1000 Venlafaxine P P P PPP Verapamil P P P PPP Vincristine P P P PPP Warfarin P P P N PP Zimelidine P P P PPP Zolpidem P P P PPP Zopiclone NNP PPP All barbiturates require an APCI source for detection.
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