Discrimination of Prohibited Oral Use of Salbutamol from Authorized Inhaled Asthma Treatment

Abstract

Background: The administration of salbutamol is permitted only by inhalation by the International Olympic Committee (IOC) for the management of asthma and exercise-induced asthma in athletes. The establishment of criteria to distinguish between the IOC authorized use (inhaled) and the IOC prohibited use (oral) of salbutamol appeared possible using simultaneous evaluation of variables based on the concentration of nonconjugated enantiomers of salbutamol excreted in urine. Methods: Urine was collected from asthmatic and nonasthmatic swimmers who had received various preexercise doses of oral (five doses of 4 mg) or inhaled (two doses of 100 μg) salbutamol. Urine was also obtained from subjects who had received the maximum dosage of inhaled salbutamol advisable for competing athletes to provide protection from exercise-induced asthma and treatment of asthma (1600 μg in 24 h, 800 μg being in the last 4 h). All samples were analyzed to determine the total amount of unchanged salbutamol excreted in urine and the ratio between the S and R enantiomers. Results: The discriminant function D = −3.776 + 1.46 × 10−3 {[S(+)] + [R(−)]} + 1.012 {[S(+)]/[R(−)]} can be used to classify data into two groups, inhaled and oral. The confirmatory criterion suggested (cutoff at D = 1.06, 4 SD from the mean D value of the inhaled distribution) has been verified in different sets of samples showing suspicious concentrations by conventional screening procedures in doping control. An 11.8% false-negative (oral classified as inhaled) rate is assumed with the confirmatory criterion proposed, but virtually no false positives (inhaled classified as oral) are obtained (<1 in 33 000). Conclusions: The overall procedure recommended is to screen all samples and to apply the confirmation criterion proposed to samples showing free racemic salbutamol concentrations >500 μg/L by gas chromatography-mass spectrometry or free + conjugated racemic salbutamol concentrations >1400 μg/L by ELISA.

Detection and characterization of betamethasone metabolites in human urine by LC‐MS/MS

“…Differences in the excretion of metabolites in urine depending on the route of administration have been described for some corticosteroids and other doping agents. [4][5][6][7][8][9][10][11][12] A detailed study of budesonide metabolism after inhaled and oral administrations resulted in the identification of 6β-hydroxy-budesonide as the best marker to distinguish these administration routes. [7,9] That metabolite has been recently adopted in WADA regulations to distinguish allowed and forbidden use of budesonide.…”

Urine concentrations of oral salbutamol in samples collected after intense exercise in endurance athletes

“…Pharmacokinetic studies of inhaled and oral salbutamol have been conducted to support the urinary threshold. [6][7][8][9][10][11][12][13] Most of these studies, however, have investigated urine concentrations of salbutamol in resting conditions in non-athletic subjects, and not after exercise in athletes. Doping testing is often performed after a training session or a competitive event, and elite athletes usually take their beta 2 -agonists prior to training or competition.…”

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

“…[6] The definition of a threshold concentration requires the performance of different administration studies in healthy subjects to assess the urinary levels of the compound after administration of allowed doses. [7][8][9][10] In spite of the high number of pharmacokinetic studies of formoterol in healthy subjects [11][12][13][14] or patients with asthma or COPD, [15] few data on urinary concentrations of formoterol after inhaled administrations are available in the literature to support the threshold value defined by WADA. [16][17][18][19] The objective of this work was to evaluate the threshold concentration of formoterol recently defined by WADA by studying urinary concentrations of the compound in healthy volunteers after inhalation of the maximum allowed dose and in samples from athletes with declared inhaled administration.…”