Airway drug pharmacokinetics via analysis of exhaled breath condensate.
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.
Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: Charles_Esther@med.unc.edu.
Charles R
CR
Esther
Cystic Fibrosis/Pulmonary Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Richard C
RC
Boucher
Parion Sciences Inc, Durham, NC 27713, USA.
M Ross
MR
Johnson
Parion Sciences Inc, Durham, NC 27713, USA.
John H
JH
Ansede
Parion Sciences Inc, Durham, NC 27713, USA.
Karl H
KH
Donn
Gilead Sciences Inc., Seattle, WA 98102, USA.
Thomas G
TG
O'Riordan
Environmental Protection Agency, Chapel Hill, NC 27599, USA.
Andrew J
AJ
Ghio
Parion Sciences Inc, Durham, NC 27713, USA.
Andrew J
AJ
Hirsh
D000280:Administration, Inhalation; D000584:Amiloride / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001944:Breath Tests; D005260:Female; D013058:Mass Spectrometry / Q000379:methods*; D012756:Sheep; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D014508:Urea / Q000378:metabolism*
D015415:Biomarkers; D026941:Sodium Channel Blockers; D000584:Amiloride; D014508:Urea
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