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Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control


Jacobson, GA and Hostrup, M and Narkowicz, CK and Nichols, DS and Walters, EH, Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control, Drug Testing and Analysis, 11, (7) pp. 950-956. ISSN 1942-7603 (2019) [Refereed Article]


Copyright Statement

2019 John Wiley & Sons, Ltd

DOI: doi:10.1002/dta.2587


Formoterol is a long‐acting beta2‐adrenoceptor agonist (LABA) used for 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 analysed by enantioselective 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 hydrolysed rac‐formoterol is warranted to account for inter‐individual differences in enantioselective glucuronidation.

Item Details

Item Type:Refereed Article
Keywords:LABA enantiomer chiral asthma
Research Division:Biomedical and Clinical Sciences
Research Group:Pharmacology and pharmaceutical sciences
Research Field:Pharmacology and pharmaceutical sciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Jacobson, GA (Associate Professor Glenn Jacobson)
UTAS Author:Narkowicz, CK (Dr Christian Narkowicz)
UTAS Author:Nichols, DS (Dr David Nichols)
UTAS Author:Walters, EH (Professor Haydn Walters)
ID Code:131533
Year Published:2019
Web of Science® Times Cited:6
Deposited By:Pharmacy
Deposited On:2019-03-21
Last Modified:2020-06-12
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