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

Morten Hostrup; Christian K Narkowicz; Sajad Habib; David S Nichols; Glenn A Jacobson

doi:10.1002/dta.2580

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

Morten Hostrup^*, Christian K Narkowicz, Sajad Habib, David S Nichols, Glenn A Jacobson

^*Corresponding author af dette arbejde

August Krogh Sektionen for Human Fysiologi

4 Citationer (Scopus)

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 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 × mg_{wet 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-PKA^Ser/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.

Originalsprog	Engelsk
Tidsskrift	Drug Testing and Analysis
Vol/bind	11
Udgave nummer	7
Sider (fra-til)	1048-1056
Antal sider	9
ISSN	1942-7603
DOI	https://doi.org/10.1002/dta.2580
Status	Udgivet - jul. 2019

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Det Natur- og Biovidenskabelige Fakultet

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10.1002/dta.2580

Citationsformater

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 et al.

I: Drug Testing and Analysis, Bind 11, Nr. 7, 07.2019, s. 1048-1056.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

@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 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.",

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}",

year = "2019",

month = jul,

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",

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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

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 -