Significance of respiratory dynamics of the lung tissue in pulmonary drug permeation.
There are two main objectives in this study. One is to investigate the roles of respiration, i.e., the dynamic change of the lung tissue, on drug transport across the air-blood barrier. The others is to establish the quantitative relationship between the effect of respiration and the physicochemical properties of drugs. To achieve these objectives, progesterone and a group of its hydroxy derivatives with varying hydrophilicity were used as the model drugs and their permeation kinetics studies were conducted under simulated respiratory dynamics using the in vitro pulmonary permeation system developed earlier in this laboratory. The physiological respiratory dynamics were successfully simulated and found to enhance significantly the transpulmonary permeation of progesterone and its hydroxy derivatives through bullfrog lung membrane, a model air-blood barrier. The extent of enhancement in the rate of drug permeation was observed to depend on the pattern of pressure application. As a pressure of the same magnitude was applied, the respiratory pressure was found to have a greater effect than a constant pressure. The results suggested that respiration has increased not only the surface area of lung membrane for permeation, but also dramatically affected the permeability of the lung membrane. Furthermore, the enhancement in permeation rate produced by respiration was observed to be in a linear correlation with the hydrophilicity of penetrants. The effect of variation in various respiratory parameters on drug permeation was also evaluated, and the results suggested that the dynamic change of the lung tissue generated by respiration plays an important role in the transpulmonary permeation of drugs. A possible mechanism involved could be attributed to the formation of transitional pores in lung membrane during the dynamic process of respiration. Therefore, it is necessary to bear in mind and take the respiratory dynamics into consideration for studying the transpulmonary permeation of drugs, especially when the drug has hydrophilic characteristics.
Yu
Jianwei
J
Department of Pharmacy Development, Wyeth-Ayerst Laboratories, Building 9A, 2 Esterbrook Lane, Cherry Hill, NJ 08003, USA.
Chien
Yie W
YW
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D006854:Hydrocortisone / Q000493:pharmacokinetics; D008168:Lung / Q000378:metabolism*; D010539:Permeability; D011312:Pressure; D011892:Rana catesbeiana; D012119:Respiration; D012995:Solubility
D002118:Calcium; D006854:Hydrocortisone