| Institution: | 1. Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;2. Cystic Fibrosis/Pulmonary Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;3. Parion Sciences Inc, Durham, NC 27713, USA;4. Gilead Sciences Inc., Seattle, WA 98102, USA;5. Environmental Protection Agency, Chapel Hill, NC 27599, USA;1. Institute of Infection, Immunity & Inflammation, University of Glasgow and Respiratory Medicine, Gartnavel General Hospital, Glasgow, UK;2. Immuno-Inflammation Therapy Area, GlaxoSmithKline, Stevenage, UK;3. Clinical Pharmacology Science and Study Operations, GlaxoSmithKline, Uxbridge, UK;4. Clinical Statistics, GlaxoSmithKline, Uxbridge, UK;5. Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge, UK;1. Laboratorio Centrale di Analisi, Dipartimento di Ricerca Traslazionale e Medicina di, Laboratorio, Istituto Giannina Gaslini, Genova, Italy;2. UOC di Pneumologia ed Allergologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy;1. Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Switzerland;2. Pulmonology, Department of Internal medicine, University Hospital Basel, Switzerland;3. Department of Thoracic Surgery, University Hospital Basel, CH-4031 Basel, Switzerland;1. Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350 Shushanhu Road, Hefei 230031, China;2. School of Science, Anhui Agricultural University, No. 130 West Changjiang Road, Hefei 230036, China;3. Anhui Province Key Laboratory of Medical Physics and Technology, No. 350 Shushanhu Road, Hefei 230031, China |
| Abstract: | Although the airway surface is the anatomic target for many lung disease therapies, measuring drug concentrations and activities on these surfaces poses considerable challenges. We tested whether mass spectrometric analysis of exhaled breath condensate (EBC) could be utilized to non-invasively measure airway drug pharmacokinetics and predicted pharmacological activities.Mass spectrometric methods were developed to detect a novel epithelial sodium channel blocker (GS-9411/P-680), two metabolites, a chemically related internal standard, plus naturally occurring solutes including urea as a dilution marker. These methods were then applied to EBC and serum collected from four (Floridian) sheep before, during and after inhalation of nebulized GS-9411/P-680. Electrolyte content of EBC and serum was also assessed as a potential pharmacodynamic marker of drug activity. Airway surface concentrations of drug, metabolites, and electrolytes were calculated from EBC measures using EBC:serum urea based dilution factors.GS-9411/P-680 and its metabolites were quantifiable in the sheep EBC, with peak airway concentrations between 1.9 and 3.4 μM measured 1 h after inhalation. In serum, only Metabolite #1 was quantifiable, with peak concentrations ～60-fold lower than those in the airway (45 nM at 1 h). EBC electrolyte concentrations suggested a pharmacological effect; but this effect was not statistical significant.Analysis of EBC collected during an inhalation drug study provided a method for quantification of airway drug and metabolites via mass spectrometry. Application of this methodology could provide an important tool in development and testing of drugs for airways diseases. |
