(R,S)-salbutamol plasma concentrations in severe asthma.

OBJECTIVE: Salbutamol is commonly delivered as a racemic mixture of pharmacologically active (R)-salbutamol and inactive (S)-salbutamol. This study investigated inactive (S)- and active (R)-salbutamol plasma levels and their relationship to dose in patients with severe asthma. METHODS: Basic demographics, racemic-salbutamol dose in the preceding 24 h, lung function tests at baseline and 1 h, and a 10 mL plasma sample were obtained from subjects presenting to the Department of Emergency Medicine with acute asthma. Plasma determinations were carried out using an LC-MS assay with solid phase extraction. RESULTS: All patients (n = 5) had detectable levels of drug in plasma with range of 0.9-7.7 and 4.7-27.4 ng/mL for (R)-salbutamol and (S)-salbutamol respectively. These were correlated to total racemic salbutamol dose. The range of the (S) : (R) ratio was 2.0-5.2, with (R)-salbutamol representing 16-33% of the total plasma concentration, which did not correlate with total salbutamol dose. CONCLUSION: Only a small fraction of total plasma salbutamol concentration was found to consist of active enantiomer in patients with an acute severe exacerbation of asthma actively undergoing treatment with racemic-salbutamol. As a result of the possible contribution of (S)-salbutamol to poor asthma control further enantioselective investigations are warranted in severe asthma.

LC-MS method for the determination of albuterol enantiomers in human plasma using manual solid-phase extraction and a non-deuterated internal standard.

A sensitive enantioselective liquid chromatography-mass spectrometry (LC-MS) assay using a manual solid-phase extraction (SPE) procedure, a non-deuterated internal standard and an ion trap LC-MS was developed to measure (R)- and (S)-albuterol in plasma. Sample extraction from plasma was achieved by a manual SPE extraction procedure with methoxyphenamine added as the internal standard. Chiral separation was achieved using a teicoplanin-based stationary phase and a mobile phase consisting of methanol, acetic acid and 28% (w/v) ammonia (1000:5:1, v/v/v). Samples were analyzed by selected reaction monitoring of product ions from the protonated molecular ions. The detection limit of the assay was 0.1 ng/ml with a conservative lower limit of quantification of 0.25 ng/ml for each enantiomer. Recovery of albuterol enantiomers from plasma spiked at 10 ng/ml of racemate was determined to be 89+/-5.8% (mean+/-S.D.). Reproducibility at 10 ng/ml of racemate assessed by the coefficient of variation was found to be 6.5% (n=5). Instrument precision (measured as coefficient of variation) was 1.4% (n=5). The correlation coefficient r(2) determined from the calibration curve over the range 0.5-50.0 ng/ml racemate in plasma was 0.998. This assay allows adequate sensitivity, recovery and reproducibility for the application to studies of inhaled albuterol.