2023 FDA Science Forum
Determination of Albuterol Sulfate using LC-MS/MS and Evaluation of Lung Microphysiological Systems Used for Inhaled Drugs
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Albuterol (salbutamol) Sulfate (SS) is an inhaled beta2-adrenergic agonist used to treat or prevent bronchospasms in patients with reversible obstructive airway disease. SS is a highly water-soluble drug (log P of < 0.4). SS was chosen as a model inhaled drug to understand how lung microphysiological systems can be used to evaluate the permeability and epithelial solubility of clinically relevant inhaled drugs. Development of a sensitive method is necessary to accurately measure low intracellular concentrations and to evaluate drug permeability. A sensitive LC-MS/MS was developed and validated for the determination of SS over a concentration range of 10-2000 nM in serum-free media (PneumaCult™-ALI Medium and Endothelial Cell Growth Basal Medium) used for lung MPS. Excellent peak shape was obtained for both analyte and internal standard using a reversed phase C18 column, 0.05:2:98 formic acid/methanol/water, v/v/v as mobile phase A methanol with 0.1% formic acid, v/v as mobile phase B, and a positive ESI MRM mode. Sample dilution with organic solvent was applied for sample processing followed by online sample clean up. SS was stable for 3 freeze/thaw cycles and for 8 hours at RT in low-binding tubes, extracted samples were stable for 29 hours at 2-8 ◦C. No light sensitivity, non-specific binding, or degradation were observed after incubation at 37 ◦C for 180 minutes in the study media. The proposed method was applied to evaluate the permeability and epithelial solubility of SS using two different lung MPS. Preliminary results showed moderate to high cell permeability and low intracellular concentrations for human lung epithelial and endothelial cells using different MPS. The results were consistent with drug properties and clinical information.
