A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease

Kharidia, Jahnavi; Fogarty, Charles; LaForce, Craig; Maier, Gary; Hsu, Roger; Dunnington, Katherine; Curry, Lisa; Baumgartner, Rudolf; Hanrahan, John P.

doi:10.1016/j.pupt.2008.03.003

Cited by 14 publications

(11 citation statements)

References 9 publications

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“…For instance, it may be that ( R,R )‐ and ( S,S )‐formoterol have differential partitioning, distribution and clearance kinetics in skeletal muscle. Such assessment, however, would require repeated muscle biopsy sampling for several hours because of the relatively long half‐life of formoterol . In addition, substantial inter‐variability exists in the pharmacokinetics of beta 2 ‐agonists, which is also reflected by the spread of the formoterol enantiomer concentrations observed in plasma and muscle in the present study.…”

Section: Discussionmentioning

confidence: 82%

“…13,17,33,34 An important consideration of the present study was that muscle concentrations of formoterol enantiomers were determined 1 hour after inhalation of two repetitive doses of rac-formoterol, consistent with time to reach maximum plasma levels (t max ). 20 Given the observation that the pharmacokinetics of individual formoterol enantiomers in plasma differ, 20,31 it is likely that (R,R)-and (S,S)-formoterol concentrations also exhibit a different time-course in muscle. For instance, it may be that (R,R)-and (S,S)-formoterol have differential partitioning, distribution and clearance kinetics in skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

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Beta₂‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Hostrup

Narkowicz

Habib

et al. 2019

Drug Testing and Analysis

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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.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Beta₂‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Hostrup

Narkowicz

Habib

et al. 2019

Drug Testing and Analysis

View full text Add to dashboard Cite

show abstract

“…It is not clear if longer exposure would have a similar outcome. However, a recent study of patients with chronic obstructive pulmonary disease showed a similar bronchodilator efficacy for (R,R)-and racemic formoterol after 14 days of treatment (24). Previous studies with guinea pig tracheal strips support the idea that (R,R)-and racemic formoterol have a similar relaxant efficacy, but, in those studies, (S,S)-formoterol had no significant effect on airway contractility (7,8).…”

Section: Discussionmentioning

confidence: 94%

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Delmotte

Sanderson

2010

Am J Respir Cell Mol Biol

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Formoterol, a long-acting b 2 -receptor agonist, is used to relieve bronchial constriction. However, formoterol is often a racemic formulation, and contains both (R,R)-and (S,S)-enantiomers. Because the activity of each isomer is poorly defined, the mechanisms by which formoterol relaxes smooth muscle cells (SMCs) of intrapulmonary airways are not well understood. Consequently, we compared the effects of (S,S)-, (R,R)-, and racemic formoterol, as well as (R)-albuterol, on the contraction and Ca 21 signaling of airway SMCs in mouse lung slices with phase-contrast and confocal microscopy. Small airways were contracted with methacholine and the associated SMCs displayed sustained Ca 21 oscillations and an increase in Ca 21 sensitivity. These contracted airways displayed a substantial, concentration-dependent relaxation in response to (R,R)-formoterol. Racemic formoterol had a similar potency as (R,R)-formoterol for relaxing airways. By contrast, (S,S)-formoterol only induced a small relaxation. In conjunction with relaxation, (R,R)-and racemic formoterol stopped and decreased the methacholineinduced Ca 21 oscillations and Ca 21 sensitivity of the SMCs, respectively, whereas (S,S)-formoterol only decreased the Ca 21 sensitivity. In these studies, (R,R)-and racemic formoterol had a similar, but much greater, potency than (R)-albuterol for relaxing mice airways. This action was quickly initiated at high concentrations by decreasing the frequency of Ca 21 oscillations, but was more usually mediated at lower concentrations by decreasing the Ca 21 sensitivity of the SMCs.

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“…There are little pharmacokinetic data for the (R;R)-and (S;S)-enantiomers, but the area under the curve and half-life after single or 14 days of dosing are similar indicating no accumulation of the (S;S) enantiomer. 25,26 As with levalbuterol and albuterol, there is a 2:1 potency ratio for (R;R)-formoterol versus the racemate on FEV1 and heart rate. 27 In a recent pediatric safety study, 3 doses of 7.5 mg/dose of arformoterol over 1 hour found no clinically important adverse effects.…”

Section: Arformoterolmentioning

confidence: 99%

Chiral Switch Drugs for Asthma and Allergies: True Benefit or Marketing Hype

Blake

Raissy

2013

Pediatric Allergy, Immunology, and Pulmonology

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A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease

Cited by 14 publications

References 9 publications

Beta₂‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Beta₂‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells

Chiral Switch Drugs for Asthma and Allergies: True Benefit or Marketing Hype

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A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease

Cited by 14 publications

References 9 publications

Beta2‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Beta2‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Effects of Formoterol on Contraction and Ca2+ Signaling of Mouse Airway Smooth Muscle Cells

Chiral Switch Drugs for Asthma and Allergies: True Benefit or Marketing Hype

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Product

Resources

About

Beta₂‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Beta₂‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

Effects of Formoterol on Contraction and Ca²⁺ Signaling of Mouse Airway Smooth Muscle Cells