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Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action.
J Pharm Biomed Anal. 2018 May 30; 154:102-107.JP

Abstract

BACKGROUND

Salmeterol (a long acting beta2-agonist) is a chiral molecule. (RR)-salmeterol is responsible for pharmacological effect, but basic knowledge of enantioselective pulmonary pharmacodynamics and pharmacokinetics of salmeterol remains unknown. There are safety concerns with (S)-enantiomers of beta2-agonists, with suggestions that these enantiomers may increase bronchial hyperresponsivneness in asthma patients.

METHODOLOGY

Horses (n = 12) received racemic (rac-) salmeterol 250 μg via inhalation. Enantioselective UPLC-MS/MS was used to determine (R)- and (S)-salmeterol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15 min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25 min respectively), and in plasma samples.

RESULTS

Physiologically relevant tissue concentrations were found for both enantiomers, with median levels greater in central than peripheral lung (equivalent to 32 and 5 mM (R)-salmeterol for central and peripheral lung respectively). Levels in PELF decreased around 50% over 15 min and enantioselective distribution was observed in the central lung with levels of (R)-salmeterol around 30% higher than (S)-salmeterol.

CONCLUSION

Salmeterol distribution is enantioselective in the central lung. This suggests duration of action is more likely associated with specific B2ADR localisation effects rather than non-specific physiochemical factors which would not be enantioselective.

Authors+Show Affiliations

School of Medicine, University of Tasmania, Hobart, Tasmania, Australia. Electronic address: glenn.jacobson@utas.edu.au.School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia.School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia.School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.Central Science Laboratory, University of Tasmania, Hobart, Tasmania, Australia.School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29544104

Citation

Jacobson, Glenn A., et al. "Salmeterol Undergoes Enantioselective Bronchopulmonary Distribution With Receptor Localisation a Likely Determinant of Duration of Action." Journal of Pharmaceutical and Biomedical Analysis, vol. 154, 2018, pp. 102-107.
Jacobson GA, Raidal S, Robson K, et al. Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action. J Pharm Biomed Anal. 2018;154:102-107.
Jacobson, G. A., Raidal, S., Robson, K., Narkowicz, C. K., Nichols, D. S., & Walters, E. H. (2018). Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action. Journal of Pharmaceutical and Biomedical Analysis, 154, 102-107. https://doi.org/10.1016/j.jpba.2018.02.048
Jacobson GA, et al. Salmeterol Undergoes Enantioselective Bronchopulmonary Distribution With Receptor Localisation a Likely Determinant of Duration of Action. J Pharm Biomed Anal. 2018 May 30;154:102-107. PubMed PMID: 29544104.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action. AU - Jacobson,Glenn A, AU - Raidal,Sharanne, AU - Robson,Kate, AU - Narkowicz,Christian K, AU - Nichols,David S, AU - Walters,E Haydn, Y1 - 2018/02/23/ PY - 2017/09/15/received PY - 2018/02/20/revised PY - 2018/02/21/accepted PY - 2018/3/16/pubmed PY - 2018/9/19/medline PY - 2018/3/16/entrez KW - Asthma KW - Chiral KW - LABA KW - PK KW - Respiratory KW - Stereochemistry SP - 102 EP - 107 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 154 N2 - BACKGROUND: Salmeterol (a long acting beta2-agonist) is a chiral molecule. (RR)-salmeterol is responsible for pharmacological effect, but basic knowledge of enantioselective pulmonary pharmacodynamics and pharmacokinetics of salmeterol remains unknown. There are safety concerns with (S)-enantiomers of beta2-agonists, with suggestions that these enantiomers may increase bronchial hyperresponsivneness in asthma patients. METHODOLOGY: Horses (n = 12) received racemic (rac-) salmeterol 250 μg via inhalation. Enantioselective UPLC-MS/MS was used to determine (R)- and (S)-salmeterol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15 min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25 min respectively), and in plasma samples. RESULTS: Physiologically relevant tissue concentrations were found for both enantiomers, with median levels greater in central than peripheral lung (equivalent to 32 and 5 mM (R)-salmeterol for central and peripheral lung respectively). Levels in PELF decreased around 50% over 15 min and enantioselective distribution was observed in the central lung with levels of (R)-salmeterol around 30% higher than (S)-salmeterol. CONCLUSION: Salmeterol distribution is enantioselective in the central lung. This suggests duration of action is more likely associated with specific B2ADR localisation effects rather than non-specific physiochemical factors which would not be enantioselective. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/29544104/Salmeterol_undergoes_enantioselective_bronchopulmonary_distribution_with_receptor_localisation_a_likely_determinant_of_duration_of_action_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0731-7085(17)32334-8 DB - PRIME DP - Unbound Medicine ER -