Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Standard

Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses. / Hostrup, Morten; Narkowicz, Christian K; Habib, Sajad; Nichols, David S; Jacobson, Glenn A.

I: Drug Testing and Analysis, Bind 11, Nr. 7, 2019, s. 1048-1056.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Hostrup, M, Narkowicz, CK, Habib, S, Nichols, DS & Jacobson, GA 2019, 'Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses', Drug Testing and Analysis, bind 11, nr. 7, s. 1048-1056. https://doi.org/10.1002/dta.2580

APA

Hostrup, M., Narkowicz, C. K., Habib, S., Nichols, D. S., & Jacobson, G. A. (2019). Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses. Drug Testing and Analysis, 11(7), 1048-1056. https://doi.org/10.1002/dta.2580

Vancouver

Hostrup M, Narkowicz CK, Habib S, Nichols DS, Jacobson GA. Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses. Drug Testing and Analysis. 2019;11(7):1048-1056. https://doi.org/10.1002/dta.2580

Author

Hostrup, Morten ; Narkowicz, Christian K ; Habib, Sajad ; Nichols, David S ; Jacobson, Glenn A. / Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses. I: Drug Testing and Analysis. 2019 ; Bind 11, Nr. 7. s. 1048-1056.

Bibtex

@article{ae0393cf26074db98e668b9cde8731d7,
title = "Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses",
abstract = "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 unexplored 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 UPLC-MS/MS (ultra-high performance liquid chromatography-mass spectrometry) 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 h 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 fibre-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 fibre-type composition.",
keywords = "Faculty of Science, Beta-adrenoceptor, Beta2-adrenoceptor, Beta-2, Arformoterol, LABA",
author = "Morten Hostrup and Narkowicz, {Christian K} and Sajad Habib and Nichols, {David S} and Jacobson, {Glenn A}",
note = "CURIS 2019 NEXS 123 This article is protected by copyright. All rights reserved.",
year = "2019",
doi = "10.1002/dta.2580",
language = "English",
volume = "11",
pages = "1048--1056",
journal = "Drug Testing and Analysis",
issn = "1942-7603",
publisher = "JohnWiley & Sons Ltd",
number = "7",

}

RIS

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

Y1 - 2019

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 unexplored 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 UPLC-MS/MS (ultra-high performance liquid chromatography-mass spectrometry) 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 h 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 fibre-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 fibre-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 unexplored 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 UPLC-MS/MS (ultra-high performance liquid chromatography-mass spectrometry) 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 h 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 fibre-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 fibre-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

VL - 11

SP - 1048

EP - 1056

JO - Drug Testing and Analysis

JF - Drug Testing and Analysis

SN - 1942-7603

IS - 7

ER -

ID: 214398380