Evaluation of the urinary threshold concentration of formoterol in sports drug testing

Abstract

The use of formoterol in sports is allowed by inhalation at the maximum recommended therapeutic dose. Recently, a threshold concentration of 30 ng.mL(-1) was defined by the World Anti-Doping Agency (WADA) to distinguish between therapeutic and forbidden use of formoterol. The objective of this work was to evaluate that threshold concentration. Concentrations of formoterol were measured in urine samples collected after administration of 18 µg of inhaled formoterol to five healthy volunteers, and in samples collected in routine doping tests belonging to athletes having declared inhaled formoterol use. Formoterol was detected up to 8 h after administration in all volunteers with concentrations up to 19.6 ng.mL(-1) . From 28 routine samples, 27 had less than 10 ng.mL(-1) of formoterol and only in one of the samples the concentration was 25 ng.mL(-1) . Therefore, administration of formoterol by inhalation at the maximum dose allowed by WADA will not produce false positive results using a threshold concentration of 30 ng.mL(-1) , and the experience up to now in routine doping tests indicates that the probability of obtaining urines with concentrations greater than 30 ng.mL(-1) is close to nil. For this reason, sports authorities should re-evaluate the need of a threshold concentration for formoterol and its practical usefulness.

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

“…The maximum recorded individual urine level (Table ) of rac ‐formoterol (free plus glucuronide) was 13.4 ng/mL which is in broad agreement with previous work that has been undertaken at higher doses . Previous reports have demonstrated a maximum concentration of 19.6 ng/mL total drug (free plus glucuronide) following a dose of 18 μg over 8 hours (one‐third of daily limit) but most routine samples were below 10 ng/mL .…”

“…This has led to criticisms that the current threshold concentration is too high and that further validation is required. 25 While our work did not correct for urine-specific gravity, other single-dose pharmacokinetic studies with high dose inhaled salbutamol has demonstrated that exercise and dehydration do affect urine concentrations compared to rest, resulting in a greater risk of exceeding the WADA decision limit, but correcting for specific gravity results in only modest improvements. 26 Although free formoterol enantiomers have been previously measured following inhalation (albeit at high dose 10 ), to our knowledge, this is the first report of total urine formoterol enantiomer levels (free plus glucuronide) following inhaled dosing, and only the second study to report total urine formoterol enantiomer levels in urine (the previous report followed oral dosing).…”

“…Similar results were observed by Deventer et al, where maximum concentration of free drug was 8.5 ng/mL following a 18 μg dose, and by Eibye et al with a maximum concentration of 25.6 ng/mL corrected for specific gravity following inhalation of repetitive doses up to 72 μg in 6 hours. This has led to criticisms that the current threshold concentration is too high and that further validation is required . While our work did not correct for urine‐specific gravity, other single‐dose pharmacokinetic studies with high dose inhaled salbutamol has demonstrated that exercise and dehydration do affect urine concentrations compared to rest, resulting in a greater risk of exceeding the WADA decision limit, but correcting for specific gravity results in only modest improvements …”

“…The maximum recorded individual urine level ( Table 2) of racformoterol (free plus glucuronide) was 13.4 ng/mL which is in broad agreement with previous work that has been undertaken at higher doses. [23][24][25] Previous reports have demonstrated a maximum concentration of 19.6 ng/mL total drug (free plus glucuronide) following a dose of 18 μg over 8 hours (one-third of daily limit) but most routine samples were below 10 ng/mL. 25 Similar results were observed by Deventer et al, 23 where maximum concentration of free drug was 8.5 ng/mL following a 18 μg dose, and by Eibye et al 24 with a maximum concentration of 25.6 ng/mL corrected for specific gravity following inhalation of repetitive doses up to 72 μg in 6 hours.…”

Annual banned‐substance review: analytical approaches in human sports drug testing

“…[109] The LC was equipped with a C-8 analytical column (2.1 x 50 mm, particle size 1.8 μm) and the triple quadrupole (QqQ) mass spectrometer was operated in positive ESI and MRM mode. [111] Urine samples were collected up to 24 h and analyzed using an earlier reported GC-MS-based detection method. Moreover, the stability of formoterol in urine under different pH conditions was tested and the target analyte was found to be stable under normal physiological and commonly applied sample storage conditions.…”