Pharmacological properties of inhaled beta2-agonists in athletes with special emphasis on Salmeterol and Terbutaline

Code: 13D12VB

Since 2010 the World Anti-Doping Agency (WADA) has changed their restrictions towards certain beta2-agonists on the prohibited list. As of 2013, the beta2-agonists salbutamol, formoterol and salmeterol are allowed by inhalation in therapeutic doses, and no longer require athletes to acquire a therapeutic use exemption. To distinguish allowed therapeutic use from supratherapeutic misuse, urinary thresholds and decision limits have been introduced for salbutamol and formoterol, but due to limited pharmacokinetic studies of salmeterol and terbutaline, no urinary thresholds has yet been established for these beta2-agonists on the prohibited list.

Detection of salmeterol in biological fluids is difficult due to very low concentrations, which only gives a window of approximately 8 to 12 hours of
detection in urine samples. However, the metabolite of salmeterol, Alpha-hydroxysalmeterol, is present in much higher concentrations in the urine than unaltered salmeterol and the metabolite may therefore be a suitable biological marker for excessive use of inhaled salmeterol.

Some athletes with asthma or exercise-induced bronchoconstriction (EIB) use combination therapy of both short and long-acting beta2-agonists. Combined inhalation of various beta2-agonists may affect the excretion of each substance. Lastly, asthmatic athletes usually take their beta2-agonists prior to or during competition and training. Therefore pharmacokinetic studies of beta2-agonists with applicability for the prohibited list should simulate sport-specific situations.

The main objective of the present study is to help establish urinary thresholds for salmeterol and terbutaline on the prohibited list as done with salbutamol and formoterol. A secondary objective is to address how combined inhalation of beta2-agonists influences the excretion of each substance in the urine. Lastly, an objective is to investigate the relationship between the specific gravity of urine samples and the concentrations of each beta2-agonist.

Main Findings: 

In Northern Europe, terbutaline is a commonly prescribed beta2-adrenoceptor agonist in treatment of asthma and exercise induced bronchoconstriction. We investigated the pharmacokinetics of single-dose inhalation of 2 or 4 mg terbutaline, oral ingestion of 10 mg terbutaline, and daily inhalation of 2 mg terbutaline for seven days in urine samples collected 0-24 h after administration in trained male subjects that had performed 90 min of cycling exercise. Terbutaline accumulated in urine after seven days of daily inhalation compared to single-dose inhalation during the first day, revealing incomplete elimination after 24 h. Urine concentrations of terbutaline were higher after inhalation of 4 mg than after oral ingestion of 10 mg during the first 4 h after administration, whereas concentrations of terbutaline were lower after inhalation of 4 mg than after oral ingestion of 10 mg 12 h after administration. It is concluded that inhalation of 2-4 mg terbutaline cannot be discriminated from 10 mg oral ingestion on the basis of urine concentrations for doping control purposes.

Salmeterol is another beta2-agonist widely used in treatment of asthma and exercise-induced bronchoconstriction among athletes. We investigated urine concentrations of salmeterol 0-24 h after therapeutic (200 µg) and supratherapeutic (400 µg) inhalation, as well as after seven days of daily therapeutic inhalation (200 µg/d) in endurance athletes who performed cycling exercise to mimic real-life doping control settings. Mean maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0, 1.6, and 2.0 ng/mL after single-dose inhalation of 400 and 200 µg, and seven consecutive days of inhalation of 200 µg, respectively. Corresponding individual maximum urine concentrations of salmeterol were 6.9, 5.0, and 4.8 ng/mL. Salmeterol was incompletely eliminated 24 h after inhalation, which should be taken into consideration if a urine threshold is introduced for this beta2-agonist.3

We further investigated urine concentrations 1½, 4 and 6 h of beta2-agonists salbutamol, terbutaline, salmeterol and formoterol after combined inhalation of all of them in endurance athletes who also performed cycling exercise. In this study, subjects completed two trials consisting of inhalation of short-acting beta2-agonists salbutamol (8 × 200 µg) and terbutaline (8 × 500 µg), or combined inhalation of short- and long-acting beta2-agonists salbutamol (8 × 200 µg), terbutaline (8 × 500 µg), salmeterol (4 × 50 µg), and formoterol (4 × 9 µg).Concentrations of salbutamol and terbutaline 1½-6 h after inhalation ranged from 124 to 2198 ng/mL and 82 to 2543 ng/mL, respectively, with 16% of samples above the decision limit for salbutamol when unadjusted for specific gravity, and 11% when adjusted for specific gravity. 
When all four beta2-agonists were inhaled, concentrations of salbutamol and terbutaline 1½-6 h after inhalation ranged from 66 to 2958 ng/mL and 44 to 3806 ng/mL, respectively, while concentrations of salmeterol and formoterol 1½-6 h after inhalation ranged from 0.0 to 5.7 ng/mL and 0.4 to 25.7 ng/mL, respectively. At no point did concentrations of formoterol exceed the decision limit. The most important finding from this study was that single-dose inhalation of 1600 µg salbutamol resulted in several samples that exceeded the current threshold and decision limit.