Tags

Type your tag names separated by a space and hit enter

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 Test Anal. 2019 Jul; 11(7):1048-1056.DT

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.

Authors+Show Affiliations

Section of Integrative Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.Discipline of Pharmacy, School of Medicine, University of Tasmania, Hobart, Australia.Section of Integrative Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.Central Science Laboratory, University of Tasmania, Hobart, Australia.Discipline of Pharmacy, School of Medicine, University of Tasmania, Hobart, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30836453

Citation

Hostrup, Morten, et al. "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, vol. 11, no. 7, 2019, pp. 1048-1056.
Hostrup M, Narkowicz CK, Habib S, et al. 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 Test Anal. 2019;11(7):1048-1056.
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
Hostrup M, et al. 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 Test Anal. 2019;11(7):1048-1056. PubMed PMID: 30836453.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2019/04/03/ PY - 2018/11/29/received PY - 2019/02/26/revised PY - 2019/02/27/accepted PY - 2019/3/6/pubmed PY - 2020/1/22/medline PY - 2019/3/6/entrez KW - LABA KW - arformoterol KW - beta-2 KW - beta-adrenoceptor KW - beta2-adrenoceptor SP - 1048 EP - 1056 JF - Drug testing and analysis JO - Drug Test Anal VL - 11 IS - 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. SN - 1942-7611 UR - https://www.unboundmedicine.com/medline/citation/30836453/Beta2__adrenergic_ligand_racemic_formoterol_exhibits_enantioselective_disposition_in_blood_and_skeletal_muscle_of_humans_and_elicits_myocellular_PKA_signaling_at_therapeutic_inhaled_doses_ L2 - https://doi.org/10.1002/dta.2580 DB - PRIME DP - Unbound Medicine ER -