Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle

Glenn A Jacobson, Kwang Choon Yee, Dino Premilovac, Stephen Rattigan

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Significant enhancement of skeletal muscle function has been observed with racemic albuterol (salbutamol). There is now general acceptance that the R-albuterol enantiomer elicits the pharmacological response, both in the lungs and extrapulmonary, while S-albuterol is pharmacologically inert. The objective of this study was to investigate the distribution of (R/S)-albuterol enantiomers into skeletal and cardiac muscle. Initially oral dosing was undertaken in neonatal mice administered a maximum tolerable dose of racemic albuterol. An in vivo infusion rat model was employed for the investigation of albuterol uptake into skeletal and cardiac muscle over 4 h. Tissue concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). From the oral dosing model, mean (±SD) levels of racemic albuterol after 5 days were 915 (±293) ng/mL in plasma, 2574 (±196) ng/g in muscle, and 53 (±6.6) ng/g in brain with enantioselective partitioning (muscle:plasma ratio of 5.7 and 1.7 for R- and S-albuterol, respectively). In the infusion model, enantioselective disposition was observed in skeletal muscle (muscle:plasma ratio of 1.2-1.7 and 0.6-0.7 for R- and S-albuterol, respectively) and in cardiac muscle (4.1 and 0.5, respectively). In conclusion, there is greater partitioning of active (R)-albuterol than inactive (S)-albuterol into both skeletal and cardiac muscle compared to plasma. These findings have relevance for albuterol sports doping, cardiac effects, and therapeutic use in muscle wasting diseases. Furthermore, the greater muscle partitioning of the active R-albuterol, and the availability of pure R-albuterol formulations highlight shortcomings in doping control measures using non-enantioselective assays.

Original languageEnglish
Pages (from-to)563-7
Number of pages5
JournalDrug Testing and Analysis
Volume6
Issue number6
DOIs
Publication statusPublished - Jun 2014

Fingerprint

Albuterol
Muscle
Myocardium
Skeletal Muscle
muscle
plasma
partitioning
Muscles
Plasmas
Enantiomers
Doping (additives)
Wasting Syndrome
sport
brain
liquid chromatography
Liquid chromatography
Therapeutic Uses
mass spectrometry
Tandem Mass Spectrometry
Sports

Cite this

Jacobson, Glenn A ; Yee, Kwang Choon ; Premilovac, Dino ; Rattigan, Stephen. / Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle. In: Drug Testing and Analysis. 2014 ; Vol. 6, No. 6. pp. 563-7.
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abstract = "Significant enhancement of skeletal muscle function has been observed with racemic albuterol (salbutamol). There is now general acceptance that the R-albuterol enantiomer elicits the pharmacological response, both in the lungs and extrapulmonary, while S-albuterol is pharmacologically inert. The objective of this study was to investigate the distribution of (R/S)-albuterol enantiomers into skeletal and cardiac muscle. Initially oral dosing was undertaken in neonatal mice administered a maximum tolerable dose of racemic albuterol. An in vivo infusion rat model was employed for the investigation of albuterol uptake into skeletal and cardiac muscle over 4 h. Tissue concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). From the oral dosing model, mean (±SD) levels of racemic albuterol after 5 days were 915 (±293) ng/mL in plasma, 2574 (±196) ng/g in muscle, and 53 (±6.6) ng/g in brain with enantioselective partitioning (muscle:plasma ratio of 5.7 and 1.7 for R- and S-albuterol, respectively). In the infusion model, enantioselective disposition was observed in skeletal muscle (muscle:plasma ratio of 1.2-1.7 and 0.6-0.7 for R- and S-albuterol, respectively) and in cardiac muscle (4.1 and 0.5, respectively). In conclusion, there is greater partitioning of active (R)-albuterol than inactive (S)-albuterol into both skeletal and cardiac muscle compared to plasma. These findings have relevance for albuterol sports doping, cardiac effects, and therapeutic use in muscle wasting diseases. Furthermore, the greater muscle partitioning of the active R-albuterol, and the availability of pure R-albuterol formulations highlight shortcomings in doping control measures using non-enantioselective assays.",
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Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle. / Jacobson, Glenn A; Yee, Kwang Choon; Premilovac, Dino; Rattigan, Stephen.

In: Drug Testing and Analysis, Vol. 6, No. 6, 06.2014, p. 563-7.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle

AU - Jacobson, Glenn A

AU - Yee, Kwang Choon

AU - Premilovac, Dino

AU - Rattigan, Stephen

N1 - Copyright © 2013 John Wiley & Sons, Ltd.

PY - 2014/6

Y1 - 2014/6

N2 - Significant enhancement of skeletal muscle function has been observed with racemic albuterol (salbutamol). There is now general acceptance that the R-albuterol enantiomer elicits the pharmacological response, both in the lungs and extrapulmonary, while S-albuterol is pharmacologically inert. The objective of this study was to investigate the distribution of (R/S)-albuterol enantiomers into skeletal and cardiac muscle. Initially oral dosing was undertaken in neonatal mice administered a maximum tolerable dose of racemic albuterol. An in vivo infusion rat model was employed for the investigation of albuterol uptake into skeletal and cardiac muscle over 4 h. Tissue concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). From the oral dosing model, mean (±SD) levels of racemic albuterol after 5 days were 915 (±293) ng/mL in plasma, 2574 (±196) ng/g in muscle, and 53 (±6.6) ng/g in brain with enantioselective partitioning (muscle:plasma ratio of 5.7 and 1.7 for R- and S-albuterol, respectively). In the infusion model, enantioselective disposition was observed in skeletal muscle (muscle:plasma ratio of 1.2-1.7 and 0.6-0.7 for R- and S-albuterol, respectively) and in cardiac muscle (4.1 and 0.5, respectively). In conclusion, there is greater partitioning of active (R)-albuterol than inactive (S)-albuterol into both skeletal and cardiac muscle compared to plasma. These findings have relevance for albuterol sports doping, cardiac effects, and therapeutic use in muscle wasting diseases. Furthermore, the greater muscle partitioning of the active R-albuterol, and the availability of pure R-albuterol formulations highlight shortcomings in doping control measures using non-enantioselective assays.

AB - Significant enhancement of skeletal muscle function has been observed with racemic albuterol (salbutamol). There is now general acceptance that the R-albuterol enantiomer elicits the pharmacological response, both in the lungs and extrapulmonary, while S-albuterol is pharmacologically inert. The objective of this study was to investigate the distribution of (R/S)-albuterol enantiomers into skeletal and cardiac muscle. Initially oral dosing was undertaken in neonatal mice administered a maximum tolerable dose of racemic albuterol. An in vivo infusion rat model was employed for the investigation of albuterol uptake into skeletal and cardiac muscle over 4 h. Tissue concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). From the oral dosing model, mean (±SD) levels of racemic albuterol after 5 days were 915 (±293) ng/mL in plasma, 2574 (±196) ng/g in muscle, and 53 (±6.6) ng/g in brain with enantioselective partitioning (muscle:plasma ratio of 5.7 and 1.7 for R- and S-albuterol, respectively). In the infusion model, enantioselective disposition was observed in skeletal muscle (muscle:plasma ratio of 1.2-1.7 and 0.6-0.7 for R- and S-albuterol, respectively) and in cardiac muscle (4.1 and 0.5, respectively). In conclusion, there is greater partitioning of active (R)-albuterol than inactive (S)-albuterol into both skeletal and cardiac muscle compared to plasma. These findings have relevance for albuterol sports doping, cardiac effects, and therapeutic use in muscle wasting diseases. Furthermore, the greater muscle partitioning of the active R-albuterol, and the availability of pure R-albuterol formulations highlight shortcomings in doping control measures using non-enantioselective assays.

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KW - Brain

KW - Bronchodilator Agents

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KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Muscle, Skeletal

KW - Myocardium

KW - Rats

KW - Rats, Wistar

KW - Stereoisomerism

KW - Tandem Mass Spectrometry

KW - Tissue Distribution

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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JO - Drug Testing and Analysis

JF - Drug Testing and Analysis

SN - 1942-7603

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