Airway drug pharmacokinetics via analysis of exhaled breath condensate.
Pulm Pharmacol Ther
; 27(1): 76-82, 2014 Feb.
Article
in En
| MEDLINE
| ID: mdl-23932897
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 EBCserum 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 â¼60-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.
Key words
EBC; Exhaled breath condensate; ICP-MS; ICP-OES; K; LC-MS/MS; MS; Na; Pharmacokinetics; SRM; Sheep; Sodium channel; Urea; exhaled breath condensate; inductively coupled plasma-mass spectrography; inductively coupled plasma-optical emission spectrography; liquid chromatography-tandem mass spectrometry; mass spectrometry; potassium; selected reaction monitoring; sodium
Full text:
1
Database:
MEDLINE
Main subject:
Mass Spectrometry
/
Urea
/
Sodium Channel Blockers
/
Amiloride
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Year:
2014
Type:
Article