34 research outputs found
Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control
Formoterol is a longâacting beta2âadrenoceptor agonist (LABA) used for treatment of asthma and exerciseâinduced bronchoconstriction. Formoterol is usually administered as a racemic (racâ) mixture of (R,R)â and (S,S)âenantiomers. While formoterol is restricted by the World AntiâDoping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 Îźg/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)âformoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 Îźg inhaled dose of racâformoterol. Urine was collected over 24âhours and analysed by enantioselective UPLCâMS/MS assay. Total (free drug plus conjugated metabolite) median (minâmax) racâformoterol urine levels following inhalation were 1.96(1.05â13.4) ng/mL, 1.67(0.16â9.67) ng/mL, 0.45(0.16â1.51) ng/mL, 0.61(0.33â0.78) ng/mL, and 0.17(0.08â1.06) ng/mL at 2, 4, 8, 12 and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)âformoterol (around 30â60% of total) compared to (S,S)âformoterol (0â30%). There was clear evidence of interâindividual enantioselectivity observed in the ratios of (R,R):(S,S)âformoterol, where (S,S)â was predominant in free formoterol, and (R,R)â predominant in the conjugated metabolite. In conclusion, racâformoterol delivered by inhalation exhibits enantioselective elimination in urine following single dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2âagonist chiral switch products such as (R,R)âformoterol, and total hydrolysed racâformoterol is warranted to account for interâindividual differences in enantioselective glucuronidation
Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular protein kinase A-signalling at therapeutic inhaled doses
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 unexplored 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 UPLC-MS/MS (ultra-high performance liquid chromatography-mass spectrometry) 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 (2Ă27 Îźg). Mean (SD) concentrations of (R,R)- and (S,S)-formoterol in plasma and in muscle biopsies of the vastus lateralis 1 h after inhalation of formoterol were 31 (15) and 45 (18) pgĂmL-1 for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pgĂmgwet wt-1, respectively, in muscle. Formoterol exhibited different enantioselective disposition in plasma and muscle (p R,R):(S,S)-formoterol ratio was lower than 0 [-0.17(0.07), p R,R):(S,S)-formoterol ratio was slightly higher than 0 [0.04(0.07), p R,R):(S,S)-formoterol ratio in muscle was related to muscle fibre-type composition. Furthermore, formoterol induced an approximately two-fold increase in muscle p-PKASer/thr phosphorylation (p 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 fibre-type composition