Isotope‐dilution mass spectrometric quantification of the prodrug lisdexamfetamine in human urine in doping control analysis
Bibliographic record
Abstract
RATIONALE: Therapeutic approaches concerning attention-deficit hyperactivity disorder (ADHD) commonly include the administration of drugs amplifying cerebral dopamine and norepinephrine signals. Among these, compounds belonging to the Prohibited List as established by the World Anti-Doping Agency (WADA) are present such as amfetamine or methylphenidate, and abuse of these can result in sanctions for athletes. The recently approved therapeutic lisdexamfetamine represents a slow-release prodrug of amfetamine for ADHD treatment. In order to support doping control laboratories in differentiating the abuse of amfetamine from a therapeutic administration of lisdexamfetamine, the determination of the prodrug from urine is desirable. Since approximately 2% of lisdexamfetamine are eliminated intact into urine, a liquid chromatography/high-resolution/high accuracy mass spectrometric method was developed, allowing the target analyte and one of its metabolites (4-hydroxyamfetamine sulfate) to be accurately quantified. METHODS: Urine samples were fortified with fourfold deuterated lisdexamfetamine and analyzed directly using ultrahigh-performance liquid chromatography (UHPLC) interfaced via electrospray ionization to a second-generation quadrupole-orbitrap mass spectrometer. The assay was characterized concerning specificity, limits of quantification (0.15-5 ng/mL), intraday and interday imprecision (4-22%), accuracy (90-120%), linearity, and ion suppression/enhancement effects. A patient's urine samples were analyzed to provide proof-of-principle data demonstrating that the intact prodrug lisdexamfetamine is detectable in urine up to 11 h post-administration at concentrations up to 80 ng/mL. Moreover, amfetamine and sulfoconjugated 4-hydroxyamfetamine were measured, yielding up to 1146 and 56 ng/mL, respectively. CONCLUSIONS: Considering the observed comparably low urinary concentrations of lisdexamfetamine and 4-hydroxyamfetamine sulfate, the preferred minimally labor-intense sample preparation, and the necessity of fast and robust result generation, the employed instrumental setup proved fit-for-purpose in sports drug testing.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".