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Development and Validation of an Ultra-Fast and Sensitive Microflow

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Development and Validation of an Ultra-Fast and Sensitive Microflow Drug Testing Research article and Analysis Received: 6 June 2016 Revised: 9 July 2016 Accepted: 10 July 2016 Published online in Wiley Online Library: 10 August 2016 (www.drugtestinganalysis.com) DOI 10.1002/dta.2042 Development and validation of an ultra-fast and sensitive microflow liquid chromatography- tandem mass spectrometry (MFLC-MS/MS) method for quantification of LSD and its metabolites in plasma and application to a controlled LSD administration study in humans Andrea E. Steuer,a* Michael Poetzsch,a Lorena Stock,a Lisa Eisenbeiss,a Yasmin Schmid,b Matthias E. Liechtib and Thomas Kraemera Lysergic acid diethylamide (LSD) is a semi-synthetic hallucinogen that has gained popularity as a recreational drug and has been investigated as an adjunct to psychotherapy. Analysis of LSD represents a major challenge in forensic toxicology due to its insta- bility, low drug concentrations, and short detection windows in biological samples. A new, fast, and sensitive microflow liquid chromatography (MFLC) tandem mass spectrometry method for the validated quantification of LSD, iso-LSD, 2-oxo 3-hydroxy- LSD (oxo-HO-LSD), and N-desmethyl-LSD (nor-LSD) was developed in plasma and applied to a controlled pharmacokinetic (PK) study in humans to test whether LSD metabolites would offer for longer detection windows. Five hundred microlitres of plasma were extracted by solid phase extraction. Analysis was performed on a Sciex Eksigent MFLC system coupled to a Sciex 5500 QTrap. The method was validated according to (inter)-national guidelines. MFLC allowed for separation of the mentioned analytes within 3 minutes and limits of quantification of 0.01 ng/mL. Validation criteria were fulfilled for all analytes. PK data could be calculated for LSD, iso-LSD, and oxo-HO-LSD in all participants. Additionally, hydroxy-LSD (HO-LSD) and HO-LSD glucuronide could be qual- itatively detected and PK determined in 11 and 8 subjects, respectively. Nor-LSD was only sporadically detected. Elimination half- lives of iso-LSD (median 12 h) and LSD metabolites (median 9, 7.4, 12, and 11 h for oxo-HO-LSD, HO-LSD, HO-LSD-gluc, and nor- LSD, respectively) exceeded those of LSD (median 4.2 h). However, screening for metabolites to increase detection windows in plasma seems not to be constructive due to their very low concentrations. Copyright © 2016 John Wiley & Sons, Ltd. Keywords: microflow LC-MS/MS; LSD; LSD metabolites; pharmacokinetics Introduction LSD consists of an ergoline skeleton in which the (5R,8R)-config- uration confers psychoactive properties. Iso-LSD is a diastereomer Lysergic acid diethylamide (LSD) is a semi-synthetic classic seroto- of LSD which was shown to be formed during the production of nergic hallucinogen derived from lysergic acid, a natural substance LSD and/or under basic conditions[9,10] and is therefore an addi- from the parasitic rye fungus Claviceps purpurea. During the 1950s, tional marker for LSD consumption.[10] The main metabolites of LSD was introduced to the medical community as an experimental LSD described in urine as further potentially ingestions markers tool to induce temporary psychotic-like states in healthy volunteers are 2-oxo-3-hydroxy-LSD (oxo-HO-LSD) and N-desmethyl-LSD (model-psychosis) and later to enhance psychotherapeutic treat- (nor-LSD).[11] Further minor metabolites detected in human urine ments (psycholytic or psychedelic therapy).[1,2] In the 1960s, it gained popularity as a recreational drug and it is still one of the most often used hallucinogenic substances worldwide.[1,3] As one * Correspondence to: Andrea E. Steuer, Department of Forensic Pharmacology and of the most potent hallucinogens, recreational LSD use in doses Toxicology, University of Zurich, Zurich Institute of Forensic Medicine (ZIFM), μ Winterthurerstrasse 190/52, CH-8057 Zurich, Switzerland. as low as 25 to 200 g are associated with significant alterations E-mail: [email protected] in consciousness. Under controlled conditions in clinical studies, – LSD is generally well tolerated.[1,4 6] Additionally, LSD has been a Department of Forensic Pharmacology and Toxicology, Zurich Institute of shown to acutely alter emotion processing in ways that may be use- Forensic Medicine, University of Zurich, Switzerland [6] ful for LSD-assisted psychotherapy. However, under uncontrolled b Psychopharmacology Research, Division of Clinical Pharmacology and 788 conditions, adverse psychological reactions including panic are Toxicology, Department of Biomedicine and Department of Clinical Research, common effects of LSD use.[7,8] University Hospital Basel, Basel, Switzerland Drug Testing New microflow LC-MS/MS method for quantification of LSD and its metabolites and application and Analysis so far were nor-iso-LSD, N-deethyl-LSD/lysergic acid ethylamide deuterated internal standard (IS) LSD-d3 (purity > 99%) were ob- (LAE), trioxylated-LSD, di-hydroxy-LSD (di-HO-LSD), lysergic acid tained from Cerilliant (delivered by Sigma-Aldrich, Buchs, ethyl-2-hydroxyethylamide (LEO), and glucuronides of 13- and 14- Switzerland). Nor-LSD (purity > 97%) was obtained as a solid from hydroxy-LSD (HO-LSD).[11,12] Analysis of LSD represents a major Toronto Research Chemicals (Toronto, Canada). Isolute HCX car- challenge in clinical and forensic toxicology especially due to its tridges (130 mg, 3 mL) were obtained from Biotage (Uppsala, instability[13–15] and rather low drug and metabolite concentrations Sweden). Water was purified with a Purelab Ultra millipore filtration in biological samples.[1,16,17] unit (Labtech, Villmergen, Switzerland) and acetonitrile of HPLC Immunoassay prescreens are typically performed in clinical and grade was obtained from Fluka (Buchs, Switzerland). All other forensic toxicology to allow for fast differentiation between negative chemicals used were from Merck (Zug, Switzerland) and of the and positive presumptive tests. However, in terms of LSD, major highest grade available. cross-reactivity is known through fentanyl or different fentanyl- [18] analogues. Applicationoffentanyliscommonasaninitialemer- Biosamples gency treatment, especially following traffic accidents. Consequently, high numbers of false-positive LSD immunoassays routinely occur. Human blank plasma samples were used for development and val- More sophisticated, confirmatory analysis on LSD detection and idation of the procedure and were obtained from healthy volun- quantification is mainly performed by gas chromatography-mass teers, collected as ammonium heparin blood, directly centrifuged spectrometry (GC-MS)[19,20] or liquid chromatography (LC)-MS(/MS) (5000 g, 15 min) and stored in aliquots at -20 ° C. techniques.[10,11,17,21–24] With these techniques, mainly LSD, iso-LSD, Plasma samples after controlled administration of LSD were col- oxo-HO-LSD, and rarely nor-LSD have been detected in urine. In lected at the University Hospital of Basel within a controlled LSD ap- [4,16] blood, LSD was the only target with rather short detection plication study to humans. Samples were stored protected windows.[25] In forensics, larger detection windows are desirable or from light at -80 °C till analysis (max. 18 months) as described in de- even necessary, especially if urine collection is impossible. Additional tail below. detection of metabolites also in blood might be an alternative but have not been investigated in detail so far. Oxo-HO-LSD was only Initial screening for LSD metabolites detected in postmortem blood[17] and recently in several emergency toxicology cases.[21] Dolder et al. were the first to determine LSD and Five plasma samples (t = 2.5 h) were initially screened for the pres- ence of the following LSD metabolites: oxo-HO-LSD, nor-LSD, HO- particularly oxo-HO-LSD pharmacokinetics (PK) in plasma after a con- [11,12] trolled 200 μg dose of LSD using a rapid turbo-flow LC-MS/MS LSD, HO-LSD glucuronide, di-HO-LSD, LAE, and LEO. Two hun- μ method.[16,21] However, despite several advantages, the method dred L of plasma were protein precipitated by the addition of μ lacked sufficient sensitivity for quantification of oxo-HO-LSD, and 600 L acetonitrile, shaken for 10 min, centrifuged (10 000 g, μ PK calculations were only possible for one-half of the participants. 10 min) and 500 L supernatant were evaporated to dryness under μ Application of newer chromatographic strategies such as nano- a gentle stream of nitrogen at 40 °C. After reconstitution in 50 L μ or microflow LC (MFLC) might offer higher sensitivity for LSD when mobile phase, 5 L were injected into an ABSciex Eksigent coupled to electrospray ionization (ESI) MS. For instance, MFLC has Microflow LC system (Redwood City, CA, USA) coupled to a Sciex been successfully applied for quantification of tetrahydrocannabi- 5500 QTrap linear ion trap quadrupole mass spectrometer (Sciex, nol (THC) in very low concentration.[26,27] In general, scaling down Darmstadt/Germany) as described below. flow rates to nano LC or MFLC systems led to certain benefits such The MFLC settings were as follows: Halo® Phenyl Hexyl column μ as reduced solvent consumption, higher throughput through de- (50 x 0.5 mm, 2.7 m), gradient elution with 10 mM ammonium for- creased run times, a higher ionization yield, and reduced ion mate buffer in water pH 3.5 (A) and acetonitrile containing 0.1% μ suppression/enhancement effects.[28,29] A previous study demon- (v/v) formic acid (B). The flow rate was 30 L/min with the following – – strated similar performance characteristics in typical validation pa- gradient: start conditions 10% B; 0 2.1 min increase to 50% B; 2.1 rameters for MFLC compared to conventional LC.[30] However, 2.23 min to 80% B, hold until 2.6 min; re-equilibrating to start condi- despite its potential benefits, in the field of clinical and forensic tox- tions of 10%B and hold for 0.3 min. Total run time was 3 min. icology such methods are currently scarce, possibly because these The MS was operated in the enhanced product ion (EPI) scan – techniques are suspected to lack ruggedness.[28–30] mode using the following settings: mass range 50 1000, scan rate The aim of the present study was the development and valida- 10 000 Da/s, dynamic trap fill time.
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