Extended Pulmonary Retention and Tissue Distribution of Inhaled Liposomal Iloprost (L608)

Abstract

Background: Inhaled liposomal iloprost (L608) shows extended plasma level for more than 12 hours in rat. In the study with hypoxia-induced pulmonary hypertension rat, L608 shows a prolonged reduction of pulmonary arterial pressure (PAP) while PAP reduction of the iloporst solution group lasted only for 2 hours at the same dose. Pulmonary distribution and retention of iloprost are thus speculated to contribute to the extended pharmacological effect.

AIM: This study is intended to compare pulmonary retention and distribution of two iloprost formulations.

Methods: Two groups of male Sprague Dawley (SD) rats were intra-tracheally (IT) administered by microsprayer with iloprost solution and liposomal iloprost (L608), respectively. The plasma, trachea primary bronchia homogenates, bronchoalveolar lavage (BAL) fluid, and lung tissues were collected at the given time points. Iloprost concentrations were determined by LC-MS-MS.

Results: Iloporst is adsorbed and entering systemic circulation quickly as shown in the solution group. There was < 0.01% of the administered dose remaining in BALF and lung tissues at 1 hour post-IT dosing. In L608 group, iloprost in BALF decreased from 32% of the administered dose at 1.5 min to 18% at 8 hours. It is noted iloprost retention in lung tissue is extended and relatively higher than the solution group. Continuous release of L608 forms drug concentration gradient from alveoli to pulmonary vascular bed.

Conclusions: The prolonged retention of L608 in BALF with slow release manner provides iloprost concentration gradient in lung tissue. It could explain the extended pharmacological effect even though drug plasma level is low.