TY - JOUR
T1 - Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses
AU - Hostrup, Morten
AU - Narkowicz, Christian K
AU - Habib, Sajad
AU - Nichols, David S
AU - Jacobson, Glenn A
N1 - CURIS 2019 NEXS 123
This article is protected by copyright. All rights reserved.
PY - 2019/7
Y1 - 2019/7
N2 - While studies have demonstrated substantial differences in beta2-adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta2-adrenergic ligand racemic (rac)-formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta2-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−1 for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg × mgwet wt−1, 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-PKASer/thr phosphorylation (p < 0.01), indicating a substantial beta2-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.
AB - While studies have demonstrated substantial differences in beta2-adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta2-adrenergic ligand racemic (rac)-formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta2-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−1 for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg × mgwet wt−1, 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-PKASer/thr phosphorylation (p < 0.01), indicating a substantial beta2-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.
KW - Faculty of Science
KW - Beta-adrenoceptor
KW - Beta2-adrenoceptor
KW - Beta-2
KW - Arformoterol
KW - LABA
U2 - 10.1002/dta.2580
DO - 10.1002/dta.2580
M3 - Journal article
C2 - 30836453
SN - 1942-7603
VL - 11
SP - 1048
EP - 1056
JO - Drug Testing and Analysis
JF - Drug Testing and Analysis
IS - 7
ER -