Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle
Jacobson, GA and Yee, KC and Premilovac, D and Rattigan, S, Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle, Drug Testing and Analysis, 6, (6) pp. 563-567. ISSN 1942-7603 (2013) [Refereed Article]
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.