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Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control.
Drug Test Anal. 2017 Aug; 9(8):1262-1266.DT

Abstract

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.

Authors+Show Affiliations

School of Medicine, University of Tasmania, Hobart, Australia.Section of Integrative Physiology, Department of Nutrition Exercise and Sports, University of Copenhagen, Denmark. Department of Respiratory Medicine, Bispebjerg University Hospital, Denmark.School of Medicine, University of Tasmania, Hobart, Australia.Central Science Laboratory, University of Tasmania, Hobart, Australia.School of Medicine, University of Tasmania, Hobart, Australia.

Pub Type(s)

Evaluation Study
Journal Article

Language

eng

PubMed ID

28033454

Citation

Jacobson, Glenn A., et al. "Enantioselective Disposition of (R)-salmeterol and (S)-salmeterol in Urine Following Inhaled Dosing and Application to Doping Control." Drug Testing and Analysis, vol. 9, no. 8, 2017, pp. 1262-1266.
Jacobson GA, Hostrup M, Narkowicz CK, et al. Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control. Drug Test Anal. 2017;9(8):1262-1266.
Jacobson, G. A., Hostrup, M., Narkowicz, C. K., Nichols, D. S., & Haydn Walters, E. (2017). Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control. Drug Testing and Analysis, 9(8), 1262-1266. https://doi.org/10.1002/dta.2131
Jacobson GA, et al. Enantioselective Disposition of (R)-salmeterol and (S)-salmeterol in Urine Following Inhaled Dosing and Application to Doping Control. Drug Test Anal. 2017;9(8):1262-1266. PubMed PMID: 28033454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control. AU - Jacobson,Glenn A, AU - Hostrup,Morten, AU - Narkowicz,Christian K, AU - Nichols,David S, AU - Haydn Walters,E, Y1 - 2016/12/29/ PY - 2016/09/01/received PY - 2016/10/26/revised PY - 2016/10/31/accepted PY - 2016/12/30/pubmed PY - 2018/5/16/medline PY - 2016/12/30/entrez KW - LABA KW - doping KW - enantiomer KW - pharmacokinetics SP - 1262 EP - 1266 JF - Drug testing and analysis JO - Drug Test Anal VL - 9 IS - 8 N2 - 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. SN - 1942-7611 UR - https://www.unboundmedicine.com/medline/citation/28033454/Enantioselective_disposition_of__R__salmeterol_and__S__salmeterol_in_urine_following_inhaled_dosing_and_application_to_doping_control_ L2 - https://doi.org/10.1002/dta.2131 DB - PRIME DP - Unbound Medicine ER -