Short inhalation exposures of the isolated and perfused rat lung to respirable dry particle aerosols; the detailed pharmacokinetics of budesonide, formoterol, and terbutaline.
There is an increasing interest in using the lung as a route of entry for both local and systemic administration of drugs. However, because adequate technologies have been missing in the preclinical setting, few investigators have addressed the detailed disposition of drugs in the lung following short inhalation exposures to highly concentrated dry powder aerosols. New methods are needed to explore the disposition of drugs after short inhalation exposures, thus mimicking a future clinical use. Our aim was to study the pulmonary disposition of budesonide, formoterol, and terbutaline, which are clinically used for the treatment of bronchial asthma. Using the recently developed DustGun aerosol technology, we exposed by inhalation for approximately 1 min the isolated and perfused rat lung (IPL) to respirable dry particle aerosols of the three drugs at high concentrations. The typical aerosol concentration was 1 mug/mL, and the particle size distribution of the tested substances varied with a MMAD ranging from 2.3 to 5.3 mum. The IPL was perfused in single pass mode and repeated samples of the perfusate were taken for up to 80 min postexposure. The concentration of drug in perfusate and in lung extracts was measured using LC-MS/MS. The deposited dose was determined by adding the amounts of drug collected in perfusate to the amount extracted from the tissues at 80 min. Deposited amounts of budesonide, formoterol fumarate, and terbutaline sulphate were 23 +/- 17, 36 +/- 8, and 60 +/- 3.2 mug (mean +/- SD, n = 3), respectively. Retention in lung tissues at the end of the perfusion period expressed as fraction of deposited dose was 0.19 +/- 0.05, 0.19 +/- 0.06, and 0.04 +/- 0.01 (mean +/- SD, n = 3) for budesonide, formoterol, and terbutaline, respectively. Each short inhalation exposure to the highly concentrated aerosols consumed 1-3 mg powder. Hence, this system can be particularly useful for obtaining a detailed pharmacokinetic characterization of inhaled compounds in drug discovery/development.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Per
P
Ewing
Stefan J
SJ
Eirefelt
Paul
P
Andersson
Anders
A
Blomgren
Ake
A
Ryrfeldt
Per
P
Gerde
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019819:Budesonide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D000068759:Formoterol Fumarate; D008168:Lung / Q000378:metabolism; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D013726:Terbutaline / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
D000336:Aerosols; D001993:Bronchodilator Agents; D004983:Ethanolamines; D019819:Budesonide; D013726:Terbutaline; D000068759:Formoterol Fumarate