Observations on the pharmacokinetics, pharmacodynamics and pulmonary deposition of Nedocromil sodium

Summers, Quentin Anthony (1991) Observations on the pharmacokinetics, pharmacodynamics and pulmonary deposition of Nedocromil sodium. University of Southampton, Doctoral Thesis.

Abstract

Nedocromil sodium (NS) is a small hydrophilic molecule active in the treatment of asthma. NS pharmacokinetics are governed by absorption of the drug across the respiratory mucosa. In asthmatics, NS inhibits bronchoconstriction induced by inhaled adenosine-5'-monophosphate (AMP). When delivered by inhalation, by mouth or by intravenous infusion to 9 atopic asthmatics, only inhaled NS conferred significant protection against inhaled AMP. In 2 subjects, both highly atopic and highly reactive to inhaled AMP, all 3 routes of NS administration provided equivalent protection, and overall there were correlations between response to AMP and the protective efficacy of NS. Therefore the preferred route of administration of NS is by inhalation, and in those with greater degrees of airways inflammation, NS may exert some effect by delivery to sites of action via the bronchial circulation. In normal subjects, both multiple forced expirations and a single deep inspiration with a prolonged breath-hold produce sudden rises in plasma NS. The likely mechanism is disruption of epithelial tight junctions, allowing the more rapid paracellular egress of drug into the bronchial circulation. Probenecid premedication did not alter the overall kinetic profile of NS, but was associated with greater rises in plasma NS after the respiratory manoeuvres. This may be a consequence of that fraction of NS absorption through the transcellular route being retarded by probenecid, resulting in more NS being available at the mucosal surface for paracellular transport, the first time that a human probenecid-sensitive facilitated transport mechanism has been shown for a drug in the human lung. Inhaled methoxamine did not alter the induced rises in plasma NS, suggesting that changes in respiratory mucosal blood flow are unlikely to be responsible for these rises, although changes in bronchial-to-pulmonaryblood flow cannot be excluded. A method was developed to add a radioisotope (technetium-99m as pertechnetate) to NS delivered by metered-dose inhaler. This produced an aerosol in which drug and label distributed together and which preserved the aerosol size characteristics. Coarse and fine radiolabelled aerosols of NS were inhaled by 10 normal subjects, and intra-pulmonary deposition studied by planar and tomographic γ-camera imaging. No differences in deposition or pharmacokinetics were found, although the fine aerosol tended to be deposited more peripherally. New techniques were developed to describe the 3-dimensional (or volume) deposition of the aerosols, both in terms of the intensity of deposition and of the dose deposited, to allow an accurate assessment of the total dose delivered to definable sites within the lung. 50% of the intrapulmonary dose of these aerosols was in the lung periphery, and in 9 subjects, the dose increased linearly from the lung hilum to periphery, but not in another subject who had predominantly central deposition. Tomography imaging is a valuable tool for showing the volume deposition of aerosols in the lung, and provides an opportunity to relate drug deposition and pharmacokinetics.

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