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Beta 2 -adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses.
- Source :
-
Drug testing and analysis [Drug Test Anal] 2019 Jul; Vol. 11 (7), pp. 1048-1056. Date of Electronic Publication: 2019 Apr 03. - Publication Year :
- 2019
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Abstract
- While studies have demonstrated substantial differences in beta <subscript>2</subscript> -adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta <subscript>2</subscript> -adrenergic ligand racemic (rac)-formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta <subscript>2</subscript> -adrenergic agonist in skeletal muscle is absent despite its promising data on muscle anabolism in humans. Using a sensitive ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay, we determined disposition of (R,R)-formoterol and (S,S)-formoterol in plasma and skeletal muscle samples from 11 non-asthmatic men who had inhaled rac-formoterol at therapeutic doses (2 × 27 μg). Mean (SD) concentrations of (R,R)- and (S,S)-formoterol in plasma and in muscle biopsies of the vastus lateralis 1 hour after inhalation of formoterol were 31 (15) and 45 (18) pg × mL <superscript>-1</superscript> for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg × mg <subscript>wet wt</subscript> <superscript>-1</superscript> , respectively, in muscle. Formoterol exhibited different enantioselective disposition in plasma and muscle (p < 0.0001). In plasma, mean log (R,R):(S,S)-formoterol ratio was lower than 0 [-0.17(0.07), p < 0.0001], whereas in muscle, mean log (R,R):(S,S)-formoterol ratio was slightly higher than 0 [0.04(0.07), p < 0.05]. Log (R,R):(S,S)-formoterol ratio in muscle was related to muscle fiber-type composition. Furthermore, formoterol induced an approximately two-fold increase in muscle p-PKA <superscript>Ser/thr</superscript> phosphorylation (p < 0.01), indicating a substantial beta <subscript>2</subscript> -adrenergic response. Collectively, these findings suggest that formoterol exhibits modest enantioselective disposition in plasma after inhaled therapy in humans, which appear related to a greater (R,R)-enantiomer disposition in skeletal muscle that may be dependent on fiber-type composition.<br /> (© 2019 John Wiley & Sons, Ltd.)
- Subjects :
- Administration, Inhalation
Adrenergic beta-2 Receptor Agonists administration & dosage
Adrenergic beta-2 Receptor Agonists blood
Adrenergic beta-2 Receptor Agonists pharmacology
Adult
Bronchodilator Agents administration & dosage
Bronchodilator Agents blood
Bronchodilator Agents pharmacology
Chromatography, High Pressure Liquid methods
Formoterol Fumarate administration & dosage
Formoterol Fumarate blood
Formoterol Fumarate pharmacology
Humans
Muscle, Skeletal metabolism
Stereoisomerism
Tandem Mass Spectrometry methods
Young Adult
Adrenergic beta-2 Receptor Agonists pharmacokinetics
Bronchodilator Agents pharmacokinetics
Cyclic AMP-Dependent Protein Kinases metabolism
Formoterol Fumarate pharmacokinetics
Muscle, Skeletal drug effects
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1942-7611
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Drug testing and analysis
- Publication Type :
- Academic Journal
- Accession number :
- 30836453
- Full Text :
- https://doi.org/10.1002/dta.2580