The Froome case: despite adherence to WADA regulations, is it physiologically possible that a urine sample can contain more than the permissible level of Salbutamol?

By Andrew J Simpson @andyjohnsimpson

Four time Tour de France champion Chris Froome returned an ‘adverse analytical finding‘, in a urine sample collected on 7th September 2017 after Stage 18 of the Vuelta a Espana. Froome denies any wrong doing, insisting he is fully aware of, and compliant with, the World Anti Doping Agency’s (WADA) regulations regarding the use of asthma medication, including the commonly used ‘reliever’ inhaler, Salbutamol. Here I address the crux of the matter — is it physiologically possible that a urine sample can contain more than the permissible level of Salbutamol despite adherence to WADA regulations?

What is the permissible level?

The permissible level of inhaled Salbutamol is 1600 μg (16 puffs of the reliever inhaler) over 24 hours and no more than 800 μg every 12 hours [1]. If the presence of Salbutamol in urine exceeds 1000 ng/mL, it is presumed not to be an intended therapeutic use and considered as an adverse analytical finding by WADA. In Froome’s case the value exceeded 2000 ng/ml. Following such a finding it becomes the athlete’s responsibility to prove, through a controlled pharmacokinetic study, that the abnormal result was the consequence of the therapeutic dose. Presumably, Froome and his team will attempt to do just this. So, what should they consider?

What do previous studies tell us about Salbutamol inhalation and urine concentrations?

Previous investigations have demonstrated that it is possible for the urine concentration of Salbutamol to be above the permissible limit [2,3]. The frequency of violations increase if the athlete completes exercise prior to the sample being taken [2,3], likely due to increased pulmonary absorption, secondary to an increase in pulmonary blood flow during exercise. Furthermore, following exercise-induced dehydration the probability of an adverse finding is increased yet again [2,3]. Froome’s results are not directly comparable here, as the dose in these studies was equivalent to the maximum daily dosage in a single hit, therefore breaching WADA regulations of more than 800 μg every 12 hours. Data regarding violations when doses were inline with these 12-hour guidelines are scarce. However, one study provides evidence of an adverse analytical finding in a single subject, albeit at much lower concentration than in Froome’s case (maximum concentration was 1057 ng/ml), when adhering to these 12 hour regulations [4]. None of these investigations provide definitive evidence for the on-going case;  however, both exercise and dehydration can significantly increase the concentration of Salbutamol in urine.

Is Froome a special case?

Froome’s case is unique, making it largely non-comparable to published literature. The characteristics Froome possesses make him an outlier in a typical study. He is capable of some astonishing feats, which the typical study participant is not. If we took the aforementioned studies that demonstrate that exercise and dehydration increase the concentration of Salbutamol in urine for example [2,3]; the intensity and duration of exercise investigated does not come close to that regularly achieved by Froome. Indeed, the previous investigations involved participants cycling at 60% of VO2 max for 75 min followed by a 20 km time trial [3] or a self-determined pace for up to 4 hours [2], durations and/or intensities well-short of that required of elite cyclists. What remains unknown therefore is whether exercise for longer durations and/or at higher intensities, and over several days/weeks, can further increase the concentration of Salbutamol in urine.

Another important consideration in the Froome case is that he has asthma and exercise-induced bronchoconstriction (EIB). The airways of people with asthma are inflamed and often damaged, and can be further injured following exercise. Indeed, shedding of the airway epithelium, a marker of airway epithelial integrity, is increased in individuals with asthma and EIB, and can be exaggerated following exercise [5]. As Salbutamol is inhaled into the lungs, it would stand to reason that higher concentrations of the drug would diffuse from the lungs into the pulmonary circulation, and ultimately the urine, in the presence of a damaged airway epithelium. However data are lacking. Furthermore, asthma is a variable lung disease, with periods where asthma is well controlled and periods of exacerbation. Asthmatics are often excluded from clinical studies during periods of exacerbation, for both logistical and safety reasons. Therefore, previous investigations suggesting that the pharmacokinetics of Salbutamol in healthy and asthmatics individuals is similar [4], may not hold true during an asthma exacerbation. At the time Froome provided the sample under investigation, he was experiencing an exacerbation of his asthma symptoms.

In conclusion, recreating the complex chain of events leading up to and on the day of the urine sample in question will not be straight forward, but Froome and his team will no doubt consider factors such as prior exercise, dehydration and asthma exacerbations at the very minimum. Additional factors such as allergies, pollutants, inhalation technique and the timing of urine collection, which were not discussed here, may also be considered.

Dr Andrew Simpson (@andyjohnsimpson) is a lecturer in Sport, Health and Exercise Science at the University of Hull. Andrew completed his PhD at Brunel University, where he investigated the Pathophysiology of Exercise-Induced Bronchoconstriction in Athletes.

References

1   The World Anti-Doping Agency. The World Anti-Doping Code International Standard. https://www.wada-ama.org/sites/default/files/resources/files/2016-09-29_-_wada_prohibited_list_2017_eng_final.pdf. Accessed December, 2017

2   Dickinson J, Hu J, Chester N, et al. Impact of ethnicity, gender, and dehydration on the urinary excretion of inhaled salbutamol with respect to doping control. Clin J Sport Med 2014;24:482–9. doi:10.1097/JSM.0000000000000072

3   Haase CB, Backer V, Kalsen A, et al. The influence of exercise and dehydration on the urine concentrations of salbutamol after inhaled administration of 1600 µg salbutamol as a single dose in relation to doping analysis. Drug Test Anal 2016;8:613–20. doi:10.1002/dta.1828

4   Elers J, Pedersen L, Henninge J, et al. The pharmacokinetic profile of inhaled and oral salbutamol in elite athletes with asthma and nonasthmatic subjects. Clin J Sport Med 2012;22:140–5. doi:10.1097/JSM.0b013e31823513e1

5   Hallstrand T, Moody MW, Wurfel MM, et al. Inflammatory basis of exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2005;172:679–86. doi:10.1164/rccm.200412-1667OC

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