Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action

Glenn A. Jacobson, Sharanne Raidal, Kate Robson, Christian K. Narkowicz, David S. Nichols, E. Haydn Walters

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)102-107
Number of pages6
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume154
DOIs
Publication statusPublished - 30 May 2018

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Lung
Enantiomers
Biopsy
Linings
Pharmacodynamics
Tissue
Salmeterol Xinafoate
Pharmacokinetics
Fluids
Inhalation
Horses
Asthma
Plasmas
Pharmacology
Molecules
Safety

Cite this

Jacobson, Glenn A. ; Raidal, Sharanne ; Robson, Kate ; Narkowicz, Christian K. ; Nichols, David S. ; Walters, E. Haydn. / Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action. In: Journal of Pharmaceutical and Biomedical Analysis. 2018 ; Vol. 154. pp. 102-107.
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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.",
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Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action. / Jacobson, Glenn A.; Raidal, Sharanne; Robson, Kate; Narkowicz, Christian K.; Nichols, David S.; Walters, E. Haydn.

In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 154, 30.05.2018, p. 102-107.

Research output: Contribution to journalArticle

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

PY - 2018/5/30

Y1 - 2018/5/30

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.

AB - 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.

KW - Asthma

KW - Chiral

KW - LABA

KW - PK

KW - Respiratory

KW - Stereochemistry

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DO - 10.1016/j.jpba.2018.02.048

M3 - Article

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JF - Journal of Pharmaceutical and Biomedical Analysis

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