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Sample Chapter LCMS_Chap09 (JB-D) 8/5/06 3:14 pm Page 193 9 LC-MS in doping control Detlef Thieme Introduction adjacent fields with similar analytical prospects, like veterinary residue control (predominantly dealing with identification of growth promoters Definition of doping in various matrices), forensic sciences (the major- ity of doping-relevant substances are scheduled Doping analysis comprises a diversity of sub- as controlled substances in most countries), stance classes with different pharmaceutical and environmental analysis (e.g. steroids in waste chemical properties. Therefore, the discussion of water) or clinical chemistry (e.g. due to the the suitability of liquid chromatography-mass increasing relevance of steroid hormone replace- spectrometry (LC-MS) in doping analysis needs ment therapy). to distinguish various categories. This chapter describes the key fields of appli- According to its formal definition, a doping cation of LC-MS in routine doping control (i.e. violation in sports can be caused by various screening analysis, confirmation and quantifica- events, e.g.: tion of positive results) extra to particular • the detection of a prohibited substance or research activities. The latter are focused on the metabolites or markers of that substance (as intended technical improvements (e.g. extension defined by the recent document [1] of the of detection time windows, reduction of turn- World Anti-Doping Agency [WADA]) in the around times and costs) of conventional analyti- athlete’s specimen cal procedures and, in particular, on the detection • the use of prohibited substances or methods of prohibited substances that cannot be ade- • possession or trafficking prohibited substances quately identified so far (e.g. growth hormone). • refusing without compelling justification to The arrangement follows mainly historical submit a sample. and technical considerations, and does not necessarily represent the frequency or relevance This definition is clearly legally motivated and of the application of LC-MS. does not support the discussion of technical issues. The number and classes of prohibited sub- LC-MS in doping control – historical and stances is very complex in human sports, where β technical aspects selected stimulants, narcotics, hormones, 2- agonists, anti-oestrogenic agents and diuretics are Some peculiar legal and technical principles in covered. The situation becomes even more con- doping control influence analytical strategies in fusing if the term ‘doping’ is extended to animal athletes drug testing: (e.g. equestrian) sports, where any application of pharmaceutical drugs is totally prohibited and • The substance-based doping definition priori- even substance classes like muscle relaxants or tises target analyses compared with general mild stimulants are included. unknown screening procedures. Sensitive and Moreover, doping analysis is closely related to specific selected ion monitoring (SIM) or 193 LCMS_Chap09 (JB-D) 8/5/06 3:14 pm Page 194 194 Chapter 9 • LC-MS in doping control selected reaction monitoring (SRM) experi- nique in anti-doping research and routine [3] ments are much more frequent than scanning analyses. The issue of peptide hormones was experiments. already tackled in the mid-1990s, because gas • Urine, which is the preferred specimen for chromatography (GC)-MS analysis could not doping control due to the ease of sample solve the problem of identification of macromol- collection and relatively high concentrations ecular compounds. The potential of LC-MS to dif- of xenobiotics, requires a careful consideration ferentiate intact growth hormone obtained from of substance metabolism, including conjuga- different manufacturers, quantify the insulin-like tion. Minor biochemical pathways leading to growth factor (IGF-1) and characterise human long-term metabolites are often more import- chorionic gonadotrophin (hCG) after tryptic ant than active parent compounds. The digestion had already been reported in 1994 [4, relevance of quantitative analyses is reduced 5]. However, these ‘proofs of principles’ demon- to a few ‘threshold substances’. This group strate the general usefulness of LC-MS for the comprises compounds that are accepted below identification of peptide hormone doping, but certain threshold concentrations, because low are not used routinely to date, mainly due to amounts may be due to a permitted adminis- sensitivity limitations. tration (e.g. inhalation of salbutamol) or an The subsequent developments were mainly endogenous origin of the substance (e.g. characterised by practical improvements. Sub- natural levels of testosterone). In general, stances (e.g. mesocarb [6]) and substance groups qualitative substance identification is a (e.g. diuretics [7]) causing severe analytical sufficient proof of a doping offence. problems (stability) or inconvenience (time- • The differentiation between substance prohi- consuming derivatisation reactions) were bition ‘in competition’ and ‘out of competi- covered by efficient LC-MS assays, while other tion’ requires modified analytical procedures screenings remained unchanged, due to the with respect to numbers of included sub- availability of well-established and validated stances and threshold concentrations. GC-MS procedures. • A major analytical challenge consists in the In contrast, there is an obvious preference to verification of the prohibited administration use LC-MS in cases of upcoming new substances of endogenous substances like testosterone, (like the ‘designer steroid’ tetrahydrogestrinone human growth hormone (hGH) or erythro- [THG] and the stimulant modafinil) or substance poietin (EPO). In such cases, minor quantita- groups (e.g. corticosteroids, included in the list of tive (e.g. amount of steroids compared with prohibited substances in 2003). endogenous precursors or biochemical There is no preferred default LC-MS instru- byproducts) or qualitative (e.g. glycosylation mentation in doping control analyses. Almost of proteins) deviations need to be identified. any technical variant of ionisation – electrospray • MS plays an outstanding role in doping ionisation (ESI), atmospheric pressure chemical analysis and was originally considered as a ionisation (APCI) or photo-ionisation (APPI) – mandatory analytical technique for confirma- has been applied in combination with quadru- tion of substance identity. Exceptions were pole (Q), ion trap (IT) or time-of-flight (TOF) mass later acknowledged in the field of peptide analysers, whether as single or tandem mass hormones. spectrometers. Certain reports of related technical develop- Approaches to the application of an LC-MS ments of LC-MS seem to be just coincidentally coupling in the framework of doping control associated with doping, e.g.: were already reported in 1981 [2], when a combination of LC-MS equipped with a moving • The introduction of isotope ratio MS linked to belt was used for MS confirmation of corticos- LC enables the identification of the origin of teroids. The relevance of LC-MS application in substances. In particular, a differentiation of doping control was ruled by practical demands, endogenous production from synthetic mat- resulting in an early implementation of the tech- erial becomes possible in principle. However, LCMS_Chap09 (JB-D) 8/5/06 3:14 pm Page 195 Small molecules 195 applications presented so far [8] are rather complex too. It summarises any substance that insensitive (requiring 400 ng substance on- may interfere with doping analysis by: column) and therefore of no practical value in • diluting the urine and accelerating excretion routine cases. (diuretics) • The introduction of Fourier-transform ion • suppression of reabsorption of xenobiotics cyclotron resonance (FTICR) MS to identify (uricosurics, e.g. probenicid) corticosteroids [9] is probably technically • manipulation of endogenous steroid profiles motivated. The high expense of this technique (administration of epitestosterone, used as an does not permit routine applications. Never- endogenous reference of urinary steroid con- theless, it is clear that high-resolution (HR)-MS centrations, is able to conceal elevated levels is essential for identification of multiply of testosterone). charged intact peptide hormones (hGH) [10]. Affordable routine instruments could greatly improve the detection and characterisation of Diuretics proteins. Additionally, progress in chromatographic separ- The main motivation to prohibit the use of ation (e.g. column switching [11], use of graphi- diuretics in sports is the intended reduction of tised carbon [12] or chiral [13] columns) needs to body mass in weight-classified sports. The second be achieved, particularly in the field of peptide reason is a masking effect. Due to forced diuresis, hormones. The improvement of ionisation the clearance of prohibited substances (e.g. ana- efficiency appears to be a crucial aspect of steroid bolic steroids) may be accelerated and the urinary analysis. Derivatisation (dansylation [14]) of concentration may drop below the detection steroids and attempts to improve APPI ionisation limit or threshold. Different types of diuretics (e.g. using anisol as dopant gas) are both specifi- (thiazide-like, loop and potassium-sparing cally focused on a sensitivity enhancement [15]. diuretics) may be distinguished on the basis of their pharmacological properties (Table 9.1). However, these classes are not differentiated with regard to their doping relevance. The first two Small molecules groups are supposed to be most efficient in doping because of their high potency. They are The majority
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