A novel technology for studying the disposition of drugs and toxicants in the lung : short inhalation exposures of the isolated and perfused rat lung to respirable dry particle aerosols

Abstract

The disposition of solutes following the deposition of inhaled substances in the lung is a complex process that proceeds along parallel paths; passive diffusion of solutes through the air/blood barrier and local metabolism followed by blood-borne clearance to the circulation. Using the isolated and perfused lung (IPL) the pulmonary disposition of inhaled particles can be studied in great detail without interference from distal organs and systemic exposure.

In this thesis the DustGun apparatus, a novel inhalation technology, was used for suspending dry powder particles to respirable aerosols for exposing the rat IPL and to fulfil the following aims; 1) to establish a method for performing short inhalation exposures to respirable particle aerosols in high concentrations 2) to study the dosimetry of increasing doses of an inhaled tobacco associated carcinogen 3) to describe the pharmacokinetics of three asthma drugs after inhalation exposure and 4) to measure the pulmonary perfusion flow rates after inhalation exposures to a corticosteroid.

1. The DustGun/IPL exposure technology was used to generate respirable aerosols from dry particles of diesel-soot, silica particles and some micronised pharmaceutical powders. The deposition of particles in the rat lung was in agreement with literature data.

2. With increasing exposures of the lung to the carcinogen Benso(a)Pyrene (BaP), both the dissolution and metabolism were gradually saturated. The local concentration of the carcinogen in the lung was ten thousand-fold higher at the site entry than the average lung concentration and with increasing exposures the relative bioactivation of BaP in the rat lung was decreased. Consequently, this may have implications for the risk assessment of carcinogens using high- to low-dose extrapolation.

3. The exposure technology was used to measure the pharmacokinetics of three asthma drugs; budesonide, formoterol and terbutaline, representing different physico-chemical properties. After short inhalation exposures of the lungs to dry particle aerosols, the solutes appeared rapidly in the perfusate. The detailed absorption was followed for 85 minutes post exposure. At the end of the experiments the amount of solute remaining in the lungs was quantified and a mass balance of the inhaled substances was determined. Using only 1-3 mg powder per exposure, it was shown that terbutaline had a much more rapid penetration of the air/blood barrier than budesonide and formoterol. Consequently, budesonide and formoterol were markedly more retained in the lung tissue than terbutaline. These characteristics are in good agreement with clinical experience of the same drugs.

4. It was also demonstrated that budesonide had a significant vasoconstrictive effect on the pulmonary circulation and that this effect was partly α-adrenoceptor mediated. These findings are supported by clinical observations of vasoconstriction reducing the blood flow in the airway mucosa after inhalation of corticosteroids.

In the treatment of lung disorders, dry powder inhalation will remain an important route for drug delivery. Thus, the exposure technology presented in this thesis is suitable for studying the disposition of drug candidates (CDs) after short inhalation exposures of the lung. The low powder consumption for the generation of respirable aerosols warrants the use of the technology in early drug discovery/development.