Aerosol delivery and spatiotemporal tissue distribution of hydroxychloroquine in rat lung.

Autor: Xia W; PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore., Kolli AR; PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, Neuchâtel CH-2000, Switzerland. Electronic address: AdityaReddy.Kolli@pmi.com., Kuczaj AK; PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, Neuchâtel CH-2000, Switzerland., Szostak J; PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, Neuchâtel CH-2000, Switzerland., Lam S; PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore., Toh WW; PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore., Purwanti A; PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore., Tan WT; PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore., Ng R; PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore., Phillips B; PMI R&D, Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore., Peitsch MC; PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, Neuchâtel CH-2000, Switzerland., Hoeng J; PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, Neuchâtel CH-2000, Switzerland.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2024 Mar 01; Vol. 194, pp. 106693. Date of Electronic Publication: 2024 Jan 04.
DOI: 10.1016/j.ejps.2024.106693
Abstrakt: Inhalation enables the delivery of drugs directly to the lung, increasing the retention for prolonged exposure and maximizing the therapeutic index. However, the differential regional lung exposure kinetics and systemic pharmacokinetics are not fully known, and their estimation is critical for pulmonary drug delivery. The study evaluates the pharmacokinetics of hydroxychloroquine in different regions of the respiratory tract for multiple routes of administration. We also evaluated the influence of different inhaled formulations on systemic and lung pharmacokinetics by identifying suitable nebulizers followed by early characterization of emitted aerosol physicochemical properties. The salt- and freebase-based formulations required different nebulizers and generated aerosol with different physicochemical properties. An administration of hydroxychloroquine by different routes resulted in varied systemic and lung pharmacokinetics, with oral administration resulting in low tissue concentrations in all regions of the respiratory tract. A nose-only inhalation exposure resulted in higher and sustained lung concentrations of hydroxychloroquine with a lung parenchyma-to-blood ratio of 386 after 1440 min post-exposure. The concentrations of hydroxychloroquine in different regions of the respiratory tract (i.e., nasal epithelium, larynx, trachea, bronchi, and lung parenchyma) varied over time, indicating different retention kinetics. The spatiotemporal distribution of hydroxychloroquine in the lung is different due to the heterogeneity of cell types, varying blood perfusion rate, clearance mechanisms, and deposition of inhaled aerosol along the respiratory tract. In addition to highlighting the varied lung physiology, these results demonstrate the ability of the lung to retain increased levels of inhaled lysosomotropic drugs. Such findings are critical for the development of future inhalation-based therapeutics, aiming to optimize target site exposure, enable precision medicine, and ultimately enhance clinical outcomes.
Competing Interests: Declaration of Competing Interest All authors were employees of Philip Morris International when this work was performed.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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