TY - JOUR

T1 - Pharmacokinetics of salmeterol and its main metabolite α-hydroxysalmeterol after acute and chronic dry powder inhalation in exercising endurance-trained men: Implications for doping control

AU - Jessen, Søren

AU - Becker, Victoria

AU - Rzeppa, Sebastian

AU - Backer, Vibeke

AU - Bengtsen, Kasper Høtoft

AU - Hullstein, Ingunn

AU - Dehnes, Yvette

AU - Hostrup, Morten

N1 - This article is protected by copyright. All rights reserved.

PY - 2021

Y1 - 2021

N2 - As of 2020, use of beta2-agonist salmeterol is restricted by the World Anti-Doping Agency (WADA) and is only permitted by inhalation at therapeutic doses not exceeding 200 μg in 24 h. In contrast to beta2-agonists salbutamol and formoterol, WADA has not established a urine threshold for salmeterol despite its muscle hypertrophic actions observed in animals. Herein, we investigated plasma (0-4 h) and urine (0-24 h) concentrations (by UHPLC-MS/MS) of salmeterol and α-hydroxysalmeterol after dry powder inhalation at supratherapeutic (400 μg) and high therapeutic (200 μg) doses, and after 7 consecutive days of therapeutic inhalation (200 μg×day-1) in 11 healthy endurance-trained men. During each trial, participants inhaled salmeterol before 1½ h moderate-intensity cycling. Mean±SD maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0±1.6, 2.1±1.5, and 2.2±1.1 ng×mL-1 for 400 μg, 200 μg, and 7 consecutive days of 200 μg, respectively, with corresponding maximum urine concentrations of α-hydroxysalmeterol being 11.6±6.1, 5.7±4.6, and 6.5±2.6 ng×mL-1. Within the relevant window for doping control (first 6 h post-inhalation), the present data (119 samples), along with 64 biobank urine samples, showed that a combined salmeterol and α-hydroxysalmeterol urine threshold with equal cut-offs of 3.3 ng×mL-1 was superior to a salmeterol-only threshold to discriminate therapeutic (200 μg) from supratherapeutic use (400 μg) with a sensitivity of 24% with 0% false positives when applying the WADA technical document (TD2019DL.v2) method of specific gravity adjustment. Thus, a combination of urine salmeterol and α-hydroxysalmeterol concentrations may be suitable for discriminating between therapeutic and supratherapeutic prohibited inhalation of salmeterol.

AB - As of 2020, use of beta2-agonist salmeterol is restricted by the World Anti-Doping Agency (WADA) and is only permitted by inhalation at therapeutic doses not exceeding 200 μg in 24 h. In contrast to beta2-agonists salbutamol and formoterol, WADA has not established a urine threshold for salmeterol despite its muscle hypertrophic actions observed in animals. Herein, we investigated plasma (0-4 h) and urine (0-24 h) concentrations (by UHPLC-MS/MS) of salmeterol and α-hydroxysalmeterol after dry powder inhalation at supratherapeutic (400 μg) and high therapeutic (200 μg) doses, and after 7 consecutive days of therapeutic inhalation (200 μg×day-1) in 11 healthy endurance-trained men. During each trial, participants inhaled salmeterol before 1½ h moderate-intensity cycling. Mean±SD maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0±1.6, 2.1±1.5, and 2.2±1.1 ng×mL-1 for 400 μg, 200 μg, and 7 consecutive days of 200 μg, respectively, with corresponding maximum urine concentrations of α-hydroxysalmeterol being 11.6±6.1, 5.7±4.6, and 6.5±2.6 ng×mL-1. Within the relevant window for doping control (first 6 h post-inhalation), the present data (119 samples), along with 64 biobank urine samples, showed that a combined salmeterol and α-hydroxysalmeterol urine threshold with equal cut-offs of 3.3 ng×mL-1 was superior to a salmeterol-only threshold to discriminate therapeutic (200 μg) from supratherapeutic use (400 μg) with a sensitivity of 24% with 0% false positives when applying the WADA technical document (TD2019DL.v2) method of specific gravity adjustment. Thus, a combination of urine salmeterol and α-hydroxysalmeterol concentrations may be suitable for discriminating between therapeutic and supratherapeutic prohibited inhalation of salmeterol.

KW - Faculty of Science

KW - Anti-doping

KW - Beta2-adrenoceptor agonists

KW - Beta-agonist

KW - LABA

KW - Pharmacology

U2 - 10.1002/dta.2978

DO - 10.1002/dta.2978

M3 - Journal article

C2 - 33210444

VL - 13

SP - 747

EP - 761

JO - Drug Testing and Analysis

JF - Drug Testing and Analysis

SN - 1942-7603

IS - 4

ER -