Influence of exercise in normal and hot ambient conditions on the pharmacokinetics of inhaled terbutaline in trained men

Kreiberg, Michael; Becker, Victoria; Jessen, Søren; Rzeppa, Sebastian; Hemmersbach, Peter; Backer, Vibeke; Hostrup, Morten

doi:10.1111/sms.12697

Cited by 10 publications

(16 citation statements)

References 36 publications

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“…Median levels following the 200 µg dose at 2 h were 1.0 and 1.1 ng/mL for (R)‐salmeterol and (S)‐salmeterol, respectively, and median enantiomers levels at 24 h were 0.21 and 0.25 ng/mL for (R)‐ and (S)‐salmeterol, respectively. These urine levels were not controlled for dilution effects, and the variation was in line with previous studies which have identified hydration and other factors as determinants of urine levels of beta2‐agonists …”

Section: Resultssupporting

confidence: 87%

Enantioselective disposition of (R)‐salmeterol and (S)‐salmeterol in urine following inhaled dosing and application to doping control

Jacobson

Hostrup

Narkowicz

et al. 2016

Drug Testing and Analysis

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Salmeterol (USAN, INN, BAN) is a long-acting beta2-adrenoceptor agonist (LABA) widely used in the treatment of airways disease. Although salmeterol is permitted via inhalation by athletes and supratherapeutic dosing may enhance performance, no urine threshold has been established by the World Anti-Doping Agency (WADA). Salmeterol is a chiral compound consisting of (R)- and (S)-enantiomers, normally administered as racemic (rac-) mixture via inhalation. Levels of rac-salmeterol in urine are often below detectable levels and there is surprisingly little information regarding the enantioselectivity of salmeterol pharmacokinetics. In this study, subjects inhaled either 50 (n = 6) or 200 µg (n = 4; generally regarded as maximum therapeutic dose) of salmeterol and urine was then collected for 24 h and analyzed by enantioselective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Maximum rac-salmeterol urine concentrations were obtained at 2 h for both doses with medians of 0.084 ng/mL after the 50 µg dose and 2.1 ng/mL after the 200 µg dose, with an individual maximum of 5.7 ng/mL. Levels were detectable at 24 h for both doses. Salmeterol displayed enantioselective pharmacokinetics, with a mean ± SD log (S):(R) = 0.055 ± 0.025 (P < 0.0001) equivalent to (S):(R) of 1.13. In conclusion, rac-salmeterol by inhalation exhibits modest enantioselectivity in urine following single dose administration and can be detected following a single 50 µg dose for up to 24 h after inhalation. The present findings are of relevance if a urine threshold limit is to be introduced for salmeterol on the list of prohibited substances. The application of an enantiomer ratio analysis may offer improved discriminatory detection capability for doping control analysis applications. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Resultssupporting

confidence: 87%

Enantioselective disposition of (R)‐salmeterol and (S)‐salmeterol in urine following inhaled dosing and application to doping control

Jacobson

Hostrup

Narkowicz

et al. 2016

Drug Testing and Analysis

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“…; Kreiberg et al . ). Such concentrations are equivalent or even higher than those observed after oral administration of 10 mg terbutaline (Elers et al .…”

Section: Methodsmentioning

confidence: 97%

Chronic β₂‐adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men

Hostrup

Onslev

Jacobson

et al. 2017

The Journal of Physiology

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Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β A) or without (HIT) daily inhalation of β -agonist (terbutaline, 4 mg dose ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β A, respectively. Proteome signature changes were different in HIT and HIT+β A (P = 0.005), wherein β -agonist caused a repression of 25 proteins in HIT+β A compared to HIT, and an upregulation of 7 proteins compared to HIT. β -Agonist repressed or even downregulated training-induced enrichment of pathways related to oxidative phosphorylation and glycogen metabolism, but upregulated pathways related to histone trimethylation and the nucleosome. Muscle contractile phenotype changed differently in HIT and HIT+β A (P ≤ 0.001), with a fast-to-slow twitch transition in HIT and a slow-to-fast twitch transition in HIT+β A. β -Agonist attenuated training-induced enhancements in maximal oxygen consumption (P ≤ 0.01) and exercise performance (6.1 vs. 11.6%, P ≤ 0.05) in HIT+β A compared to HIT. These findings indicate that daily β -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome signature towards a fast-twitch phenotype.

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“…The outcome was that after 130 minutes of cycling, urinary concentrations of terbutaline were significantly higher than after resting and this difference remained statistically significant, even when correction for urinary SG was applied. 29 Thus there is sound evidence that exercise increases the urinary excretion both salbutamol and terbutaline.…”

Section: Exercise Increases Urinary Concentrations Of Beta-2 Agonistsmentioning

confidence: 99%

Does the urinary concentration of an inhaled beta‐2 agonist always reflect the inhaled dose and method of administration?

Fitch

2018

Drug Testing and Analysis

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The urinary threshold of 1000 ng/mL for salbutamol was established by the International Olympic Committee (IOC) in 2001 following a study that was not undertaken for that purpose. At least 25 athletes have exceeded this concentration and some after inhaling no more than the permitted daily maximum dose of 1600 μg. However, there is concern that some providing expert evidence and tribunal members hearing such cases are unaware of the occasional unpredictability of the pharmacokinetics of beta‐2 agonists. The World Anti‐Doping Agency's (WADA's) change from 1 March 2018 to allow correction of urinary specific gravity (SG) down to 1.020 for prohibited substances with a urinary threshold is a major advance and will assist in some instances. However, future cases are anticipated to occur when athletes unexpectedly exceed the urinary threshold for salbutamol after inhaling no more than the allowable dose and within WADA's stated time frame. They will then be required to appear before doping tribunals. The rapidity by which salbutamol is inhaled can influence the resultant urinary concentration and is yet to be addressed adequately in WADA's 2019 Prohibited List. The list's recommended pharmacokinetic study fails to replicate the circumstances that prevailed when the athlete was competing and the adverse analytical finding (AAF) occurred. Tribunals, and experts who advise them, need to be cognizant that the urinary concentration of salbutamol does not invariably reflect the inhaled dose and that a high urinary salbutamol concentration is not always ipso facto evidence of super‐dosing with inhaled salbutamol.

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Influence of exercise in normal and hot ambient conditions on the pharmacokinetics of inhaled terbutaline in trained men

Cited by 10 publications

References 36 publications

Enantioselective disposition of (R)‐salmeterol and (S)‐salmeterol in urine following inhaled dosing and application to doping control

Enantioselective disposition of (R)‐salmeterol and (S)‐salmeterol in urine following inhaled dosing and application to doping control

Chronic β₂‐adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men

Does the urinary concentration of an inhaled beta‐2 agonist always reflect the inhaled dose and method of administration?

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Influence of exercise in normal and hot ambient conditions on the pharmacokinetics of inhaled terbutaline in trained men

Cited by 10 publications

References 36 publications

Enantioselective disposition of (R)‐salmeterol and (S)‐salmeterol in urine following inhaled dosing and application to doping control

Enantioselective disposition of (R)‐salmeterol and (S)‐salmeterol in urine following inhaled dosing and application to doping control

Chronic β2‐adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men

Does the urinary concentration of an inhaled beta‐2 agonist always reflect the inhaled dose and method of administration?

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Chronic β₂‐adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men