Current role of LC-MS(/MS) in doping control

AbstractLiquid chromatography–(tandem) mass spectrometry [(LC-MS(/MS)] has become an integral part of modern sports drug testing as it offers unique capabilities complementing immunological and gas chromatography–(tandem) mass spectrometry [(GC-MS(/MS)]-based detection methods for prohibited compounds. The improved options of fast and sensitive targeted analysis as well as untargeted screening procedures utilizing high resolution/high accuracy mass spectrometry have considerably expanded the tools available to anti-doping laboratories for initial testing and confirmation methods. One approach is to focus on pre-selected target analytes that are measured with utmost specificity and sensitivity using diagnostic precursor–product ion pairs in low resolution tandem mass spectrometers. The other scenario is to measure and plot extracted ion chromatograms of protonated or deprotonated molecules as well as product ions as recorded in the full scan mode with high resolution/high accuracy mass spectrometry. Examples of recent applications of sports drug testing procedures published between 2007 and 2010 are presented and discussed, outlining the particular advantages of the selected approaches as well as their limitations in a short- and long-term perspective. FigureThe utility of LC-MS(/MS) in current sports drug testing programs is discussed and trends in doping control methods as well as data mining are presented

[1]  H. Northoff,et al.  Artificial Oxygen Carriers - The New Doping Threat in Endurance Sport? , 2001, International journal of sports medicine.

[2]  S. Stein,et al.  On the risk of false positive identification using multiple ion monitoring in qualitative mass spectrometry: Large-scale intercomparisons with a comprehensive mass spectral library , 2006, Journal of the American Society for Mass Spectrometry.

[3]  J. Loo,et al.  Application of mass spectrometry for target identification and characterization , 1999, Medicinal research reviews (Print).

[4]  M. Thevis,et al.  Aryl-Propionamide-Derived Selective Androgen Receptor Modulators: Liquid Chromatography-Tandem Mass Spectrometry Characterization of the in Vitro Synthesized Metabolites for Doping Control Purposes , 2008, Drug Metabolism and Disposition.

[5]  R. Wolfe.  Regulation of skeletal muscle protein metabolism in catabolic states , 2005, Current opinion in clinical nutrition and metabolic care.

[6]  M. Thevis,et al.  Quantification of human insulin-like growth factor-1 and qualitative detection of its analogues in plasma using liquid chromatography/electrospray ionisation tandem mass spectrometry. , 2008, Rapid communications in mass spectrometry : RCM.

[7]  M. Thevis,et al.  Characterization of chemically modified steroids for doping control purposes by electrospray ionization tandem mass spectrometry. , 2005, Journal of mass spectrometry : JMS.

[8]  M. Thevis,et al.  Mass spectrometric determination of gonadotrophin-releasing hormone (GnRH) in human urine for doping control purposes by means of LC-ESI-MS/MS. , 2008, Journal of mass spectrometry : JMS.

[9]  M. T. A. W. Schanzer.  Mass Spectrometry in Doping Control Analysis , 2005 .

[10]  M. Thevis,et al.  Determination of N-Desmethyl- and N-Bisdesmethyl Metabolites of Sibutramine in Doping Control Analysis Using Liquid Chromatography-Tandem Mass Spectrometry , 2006, European journal of mass spectrometry.

[11]  J R Yates,et al.  Database searching using mass spectrometry data , 1998, Electrophoresis.

[12]  M. Thevis,et al.  Mass spectrometric identification and characterization of a new long-term metabolite of metandienone in human urine. , 2006, Rapid communications in mass spectrometry : RCM.

[13]  J. Dalton,et al.  Discovery and therapeutic promise of selective androgen receptor modulators. , 2005, Molecular interventions.

[14]  P. Van Eenoo,et al.  Criteria in Chromatography and Mass Spectrometry – a Comparison Between Regulations in the Field of Residue and Doping Analysis , 2004 .

[15]  M. Thevis,et al.  Identification and Quantification of the Osmodiuretic Mannitol in Urine for Sports Drug Testing Using Gas Chromatography-Mass Spectrometry , 2008, European journal of mass spectrometry.

[16]  M. Thevis,et al.  Screening for 2-quinolinone-derived selective androgen receptor agonists in doping control analysis. , 2007, Rapid communications in mass spectrometry : RCM.

[17]  A. Makarov,et al.  Mass spectrometry of stanozolol and its analogues using electrospray ionization and collision-induced dissociation with quadrupole-linear ion trap and linear ion trap-orbitrap hybrid mass analyzers. , 2005, Rapid communications in mass spectrometry : RCM.

[18]  M. Donike,et al.  Die selektive Derivatisierung unter kontrollierten Bedingungen: Ein Weg zum Spuren-Nachweis von Aminen , 1976 .

[19]  H. Maurer.  Systematic toxicological analysis of drugs and their metabolites by gas chromatography-mass spectrometry. , 1992, Journal of chromatography.

[20]  Ó. Pozo,et al.  Efficient approach for the comprehensive detection of unknown anabolic steroids and metabolites in human urine by liquid chromatography-electrospray-tandem mass spectrometry. , 2008, Analytical chemistry.

[21]  M. Thevis,et al.  Detection of Stanozolol and Its Major Metabolites in Human Urine by Liquid Chromatography-Tandem Mass Spectrometry , 2006 .

[22]  Frank T Peters,et al.  Toward High-Throughput Drug Screening Using Mass Spectrometry , 2005, Therapeutic drug monitoring.

[23]  Wilhelm Schänzer,et al.  Mass spectrometric determination of insulins and their degradation products in sports drug testing. , 2008, Mass spectrometry reviews.

[24]  Lucia Politi,et al.  Applications of liquid chromatography-mass spectrometry in doping control. , 2005, Journal of analytical toxicology.

[25]  R. Wolfe.  Effects of insulin on muscle tissue , 2000, Current opinion in clinical nutrition and metabolic care.

[26]  M. Wilm,et al.  Error-tolerant identification of peptides in sequence databases by peptide sequence tags. , 1994, Analytical chemistry.

[27]  Duane D. Miller,et al.  Nonsteroidal tissue selective androgen receptor modulators: a promising class of clinical candidates , 2005 .

[28]  F. Botrè,et al.  A fast liquid chromatographic/mass spectrometric screening method for the simultaneous detection of synthetic glucocorticoids, some stimulants, anti-oestrogen drugs and synthetic anabolic steroids. , 2006, Rapid communications in mass spectrometry : RCM.

[29]  J. Yates,et al.  An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database , 1994, Journal of the American Society for Mass Spectrometry.

[30]  Michael J MacCoss,et al.  Computational analysis of shotgun proteomics data. , 2005, Current opinion in chemical biology.

[31]  Suhua Chang,et al.  A novel scoring schema for peptide identification by searching protein sequence databases using tandem mass spectrometry data , 2006, BMC Bioinformatics.

[32]  M. Thevis,et al.  Mass spectrometry of selective androgen receptor modulators. , 2008, Journal of mass spectrometry : JMS.

[33]  M. Thevis,et al.  Doping Control Analysis of Methoxyphenamine Using Liquid Chromatography-Tandem Mass Spectrometry , 2008, European journal of mass spectrometry.

[34]  Hans H Maurer,et al.  Position of chromatographic techniques in screening for detection of drugs or poisons in clinical and forensic toxicology and/or doping control , 2004, Clinical chemistry and laboratory medicine.

[35]  J. Tabet,et al.  N-terminal adducts of bovine hemoglobin with glutaraldehyde in a hemoglobin-based oxygen carrier. , 2005, Analytical Chemistry.

[36]  M. Thevis,et al.  Examples of doping control analysis by liquid chromatography-tandem mass spectrometry: ephedrines, beta-receptor blocking agents, diuretics, sympathomimetics, and cross-linked hemoglobins. , 2005, Journal of chromatographic science.

[37]  S. Stein,et al.  Establishing the fitness for purpose of mass spectrometric methods , 2003, Journal of the American Society for Mass Spectrometry.

[38]  M. Thevis,et al.  Quantification of Clenbuterol in Human Plasma and Urine by Liquid Chromatography-Tandem Mass Spectrometry , 2005 .

[39]  Ian R. Whittall,et al.  A demonstration of the use of ultra-performance liquid chromatography-mass spectrometry [UPLC/MS] in the determination of amphetamine-type substances and ketamine for forensic and toxicological analysis. , 2006, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[40]  M. T. A. W. Schanzer.  Identification and Characterization of Peptides and Proteins in Doping Control Analysis , 2005 .

[41]  Ó. Pozo,et al.  Development and validation of a qualitative screening method for the detection of exogenous anabolic steroids in urine by liquid chromatography-tandem mass spectrometry , 2007, Analytical and bioanalytical chemistry.

[42]  M. Ashenden,et al.  Doping with Artificial Oxygen Carriers , 2004, Sports medicine.

[43]  Duane D. Miller,et al.  Favorable effects of weak acids on negative-ion electrospray ionization mass spectrometry. , 2004, Analytical chemistry.

[44]  M. Thevis,et al.  Mass spectrometric analysis of androstan-17β-ol-3-one and androstadiene-17β-ol-3-one isomers , 2005 .

[45]  Yu-Chen Chang,et al.  Tetrahydrogestrinone: discovery, synthesis, and detection in urine. , 2004, Rapid communications in mass spectrometry : RCM.

[46]  N. Robinson,et al.  Possible origins of undetectable EPO in urine samples. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[47]  M. Thevis,et al.  Determination of Selected Stimulants in Urine for Sports Drug Analysis by Solid Phase Extraction via Cation Exchange and Means of Liquid Chromatography-Tandem Mass Spectrometry , 2008, European journal of mass spectrometry.

[48]  A. Latiff,et al.  Immunoaffinity extraction and tandem mass spectrometric analysis of human chorionic gonadotropin in doping analysis. , 2003, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[49]  P. Sönksen,et al.  Growth hormone, IGF‐I and insulin and their abuse in sport , 2008, British journal of pharmacology.

[50]  Wilhelm Schänzer,et al.  Doping control analysis of intact rapid-acting insulin analogues in human urine by liquid chromatography-tandem mass spectrometry. , 2006, Analytical chemistry.

[51]  R. Aebersold,et al.  Mass spectrometry-based proteomics , 2003, Nature.

[52]  M. Nielen,et al.  Liquid chromatographic-mass spectrometric analysis of glucuronide-conjugated anabolic steroid metabolites: method validation and interlaboratory comparison. , 2008, Journal of mass spectrometry : JMS.

[53]  P. Hemmersbach.  History of mass spectrometry at the Olympic Games. , 2008, Journal of mass spectrometry : JMS.

[54]  K. Deventer,et al.  Screening for anabolic steroids in doping analysis by liquid chromatography/electrospray ion trap mass spectrometry. , 2006, Biomedical chromatography : BMC.

[55]  M. Thevis,et al.  Doping control analysis of tricyclic tetrahydroquinoline-derived selective androgen receptor modulators using liquid chromatography/electrospray ionization tandem mass spectrometry. , 2008, Rapid communications in mass spectrometry : RCM.

[56]  M. Thevis,et al.  Determination of Synacthen in human plasma using immunoaffinity purification and liquid chromatography/tandem mass spectrometry. , 2006, Rapid communications in mass spectrometry : RCM.

[57]  J. V. Sancho,et al.  Collision-induced dissociation of 3-keto anabolic steroids and related compounds after electrospray ionization. Considerations for structural elucidation. , 2008, Rapid communications in mass spectrometry : RCM.

[58]  M. Thevis,et al.  Screening for unknown synthetic steroids in human urine by liquid chromatography-tandem mass spectrometry. , 2005, Journal of mass spectrometry : JMS.

[59]  R. Kostiainen,et al.  Screening of free 17-alkyl-substituted anabolic steroids in human urine by liquid chromatography–electrospray ionization tandem mass spectrometry , 2004, Steroids.

[60]  R. de la Torre,et al.  Stimulants, narcotics and beta-blockers: 25 years of development in analytical techniques for doping control. , 1996, Journal of chromatography. B, Biomedical applications.

[61]  M. Thevis,et al.  Mass spectrometry in sports drug testing: Structure characterization and analytical assays. , 2007, Mass spectrometry reviews.

[62]  Peter H. Sönksen,et al.  Insulin, growth hormone and sport. , 2001 .

[63]  J. Tabet,et al.  Simple identification of a cross-linked hemoglobin by tandem mass spectrometry in human serum. , 2004, Analytical Chemistry.

[64]  M. Garle,et al.  A high-throughput multicomponent screening method for diuretics, masking agents, central nervous system (CNS) stimulants and opiates in human urine by UPLC-MS/MS. , 2008, Journal of mass spectrometry : JMS.

[65]  M. Thevis,et al.  Screening for metabolically stable aryl-propionamide-derived selective androgen receptor modulators for doping control purposes. , 2006, Rapid communications in mass spectrometry : RCM.

[66]  M. Thevis,et al.  Proteases in Doping Control Analysis , 2007, International journal of sports medicine.

[67]  C. Howe,et al.  Methodologies for detection of hemoglobin-based oxygen carriers. , 2005, Journal of chromatographic science.

[68]  Ó. Pozo,et al.  Elucidation of urinary metabolites of fluoxymesterone by liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. , 2008, Journal of mass spectrometry : JMS.

[69]  J. Veuthey,et al.  Profiling of 19-norsteroid sulfoconjugates in human urine by liquid chromatography mass spectrometry. , 2008, Analytica Chimica Acta.

[70]  M. MacCoss,et al.  Shotgun proteomics: tools for the analysis of complex biological systems. , 2002, Current opinion in molecular therapeutics.

[71]  John R Yates,et al.  Large Scale Protein Profiling by Combination of Protein Fractionation and Multidimensional Protein Identification Technology (MudPIT)* , 2006, Molecular & Cellular Proteomics.

[72]  M. Mazzarino,et al.  A screening method for the simultaneous detection of glucocorticoids, diuretics, stimulants, anti-oestrogens, beta-adrenergic drugs and anabolic steroids in human urine by LC-ESI-MS/MS , 2008, Analytical and bioanalytical chemistry.

[73]  V. A. Semenov,et al.  Validation of liquid chromatography-electrospray ionization ion trap mass spectrometry method for the determination of mesocarb in human plasma and urine. , 2005, Journal of chromatographic science.

[74]  Laurent Rivier,et al.  Criteria for the identification of compounds by liquid chromatography–mass spectrometry and liquid chromatography–multiple mass spectrometry in forensic toxicology and doping analysis , 2003 .

[75]  Wilhelm Schänzer,et al.  Recommended criteria for the mass spectrometric identification of target peptides and proteins (<8 kDa) in sports drug testing. , 2007, Rapid communications in mass spectrometry : RCM.

[76]  M. Thevis,et al.  N-methyl-N-Trimethylsilyltrifluoroacetamide-Promoted Synthesis and Mass Spectrometric Characterization of Deuterated Ephedrines , 2004, European Journal of Mass Spectrometry.

[77]  R. Ventura,et al.  High-Throughput and Sensitive Screening by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry of Diuretics and other Doping Agents , 2008, European journal of mass spectrometry.

[78]  F. Botrè,et al.  A screening method for the detection of synthetic glucocorticosteroids in human urine by liquid chromatography–mass spectrometry based on class-characteristic fragmentation pathways , 2008, Analytical and bioanalytical chemistry.

[79]  M. Nielen,et al.  Urine testing for designer steroids by liquid chromatography with androgen bioassay detection and electrospray quadrupole time-of-flight mass spectrometry identification. , 2006, Analytical chemistry.

[80]  M. Thevis,et al.  Mass spectrometry of hydantoin-derived selective androgen receptor modulators. , 2008, Journal of mass spectrometry : JMS.

[81]  J. Loo.  The tools of proteomics. , 2003, Advances in protein chemistry.

[82]  Wilhelm Schänzer,et al.  Qualitative determination of synthetic analogues of insulin in human plasma by immunoaffinity purification and liquid chromatography-tandem mass spectrometry for doping control purposes. , 2005, Analytical chemistry.

[83]  D. Stratmann,et al.  Gaschromatographischer nachweis von stickstoffhaltigen pharmaka in wässrigen lösungen mit dem stickstoffdetektor , 1970 .

[84]  K. Deventer,et al.  Screening for amphetamine and amphetamine-type drugs in doping analysis by liquid chromatography/mass spectrometry. , 2006, Rapid communications in mass spectrometry : RCM.

[85]  M. Thevis,et al.  Doping control analysis of bovine hemoglobin-based oxygen therapeutics in human plasma by LC-electrospray ionization-MS/MS. , 2003, Analytical chemistry.

[86]  M. Thevis,et al.  Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC–MS/MS , 2008, Analytical and bioanalytical chemistry.

[87]  E. Virus,et al.  Introduction of HPLC/orbitrap mass spectrometry as screening method for doping control. , 2008, Journal of mass spectrometry : JMS.

[88]  Richard D. Smith,et al.  Proteome analysis by mass spectrometry. , 2003, Annual review of biophysics and biomolecular structure.