Shao Jie, Wang Yaning, Hochhaus Guenther
Department of Pharmaceutics, College of Pharmacy, University of Florida, 1225 Center Dr., Gainesville, FL 32610, USA.
Eur J Pharm Sci. 2021 Apr 1;159:105699. doi: 10.1016/j.ejps.2021.105699. Epub 2021 Jan 12.
The objective of this study was to describe the pulmonary targeting of beclomethasone dipropionate (BDP) and its active metabolite beclomethasone 17-monopropionate (BMP) in rats using a semi-mechanistic PK/PD model.
Rat plasma and tissue concentrations of BDP and BMP, and tissue receptor occupancies of BMP after systemic and pulmonary delivery of BDP and BMP were integrated in a newly developed semi-mechanistic PK/PD model.
After IV administration of BDP, 95.4% of BDP was converted to BMP, while after pulmonary delivery of BDP, 46.6% of deposited BDP was absorbed as BMP. The developed semi-mechanistic PK model described plasma and tissue concentrations of BDP and BMP as well as receptor occupancies sufficiently well. The model incorporated dissolution, metabolic activation, and drug absorption processes to describe the local fate of BDP and BMP after systemic and pulmonary delivery. Dissolution rate constants of BDP and BMP were estimated to be 0.47/h and 2.01/h, respectively, and the permeabilities in central lung were estimated to be 15.0 and 2.9 × 10 cm/s for BDP and BMP, respectively. The EC of the binding of BMP to to the receptor was estimated to be 0.0017 ng/ml. Overall, receptor occupancies in the lung were more pronounced than those in the systemic circulation after pulmonary delivery of BDP or BMP. Simulations using the developed semi-mechanistic PK/PD model demonstrated that a slow dissolution rate and low permeability can improve pulmonary targeting.
A semi-mechanistic model was developed to describe the fate of an inhaled glucocorticoid pro-drug and its active metabolite in lung and the systemic circulation, both after pulmonary and systemic administration , thereby facilitating the understanding of the complex interplay between drug, prodrug and pharmacodynamic properties for quantifying the degree pulmonary targeting.
本研究的目的是使用半机制性药代动力学/药效学（PK/PD）模型描述大鼠体内二丙酸倍氯米松（BDP）及其活性代谢物17-单丙酸倍氯米松（BMP）的肺部靶向作用。
将BDP和BMP经全身和肺部给药后大鼠血浆和组织中BDP和BMP的浓度，以及BMP的组织受体占有率整合到一个新开发的半机制性PK/PD模型中。
静脉注射BDP后，95.4%的BDP转化为BMP，而肺部给药BDP后，46.6%沉积的BDP以BMP形式被吸收。所开发的半机制性PK模型能够很好地描述BDP和BMP的血浆和组织浓度以及受体占有率。该模型纳入了溶解、代谢活化和药物吸收过程，以描述BDP和BMP经全身和肺部给药后的局部转归。BDP和BMP的溶解速率常数分别估计为0.47/h和2.01/h，BDP和BMP在肺中央的渗透率分别估计为15.0和2.9×10 cm/s。BMP与受体结合的EC估计为0.0017 ng/ml。总体而言，BDP或BMP肺部给药后，肺部的受体占有率比全身循环中的更明显。使用所开发的半机制性PK/PD模型进行的模拟表明，缓慢的溶解速率和低渗透率可改善肺部靶向性。
开发了一个半机制性模型来描述吸入性糖皮质激素前药及其活性代谢物在肺部和全身循环中的转归，包括肺部和全身给药后，从而有助于理解药物、前药和药效学性质之间的复杂相互作用，以量化肺部靶向程度。
