While studies have demonstrated substantial differences in beta(2)-adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta(2)-adrenergic ligand racemic (rac)-formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta(2)-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 x 27 mu g). 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 x mL(-1) for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg x 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 beta(2)-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.
