Enantioselective disposition of (<i>R,R</i>)‐formoterol, (<i>S,S</i>)‐formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control
Bibliographic record
Abstract
Formoterol is a long-acting beta2-adrenoceptor agonist (LABA) used for the treatment of asthma and exercise-induced bronchoconstriction. Formoterol is usually administered as a racemic (rac-) mixture of (R,R)- and (S,S)-enantiomers. While formoterol is restricted by the World Anti-Doping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 μg/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)-formoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 μg inhaled dose of rac-formoterol. Urine was collected over 24 hours and analyzed by enantioselective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay. Total (free drug plus conjugated metabolite) median (min-max) rac-formoterol urine levels following inhalation were 1.96 (1.05-13.4) ng/mL, 1.67 (0.16-9.67) ng/mL, 0.45 (0.16-1.51) ng/mL, 0.61 (0.33-0.78) ng/mL, and 0.17 (0.08-1.06) ng/mL at 2, 4, 8, 12, and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)-formoterol (around 30%-60% of total) compared to (S,S)-formoterol (0%-30%). There was clear evidence of inter-individual enantioselectivity observed in the ratios of (R,R):(S,S)-formoterol, where (S,S)- was predominant in free formoterol, and (R,R)- predominant in the conjugated metabolite. In conclusion, rac-formoterol delivered by inhalation exhibits enantioselective elimination in urine following single-dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2-agonist chiral switch products such as (R,R)-formoterol, and total hydrolyzed rac-formoterol is warranted to account for inter-individual differences in enantioselective glucuronidation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".