Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs

Abstract

Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life ϳ3.5 h), mostly attributable to progressive metabolism to dinor-and tetranoriloprost. Inhaled iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability ϳ63%). Compared with infused iloprost, significantly more rapid metabolism to dinorand tetranoriloprost was noted for iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact iloprost displays the same clearance rate as directly perfusateadmixed prostanoid. We conclude that a high percentage of inhaled iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing iloprost via ␤-oxidation, and more rapid appearance of dinor-and tetranoriloprost is noted for the inhalative as compared with the intravascular route of iloprost administration.

Evaluation of pulmonary vascular response to inhaled iloprost in heart transplant candidates with pulmonary venous hypertension

“…This can be detected by a fall in the PVR/SVR ratio from an initial 0.22 to 0.14 and by the nonlife-threatening but nevertheless significant fall in the mean arterial pressure from 85 mm Hg to 77 mm Hg and a tendential fall in systemic resistance from 1660 to 1390 dyn·s·cm − 5 . The systemic effect is attributable to a spilling over of the substance into the systemic circulation, which would also tally with the results of a lung perfusion study in the isolated rabbit lung [30], using inhaled iloprost, and a comparative study of various nebulizer systems by Olschewski et al [29]. In our study cohort, a marked fall in pulmonary capillary wedge pressure was recorded in some cases on inhaled iloprost as a result of the fall in systemic afterload.…”

Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors

“…This difference is most likely due to some species variance in the kinetics of the iloprost catabolic pathway: being chemically stable – in contrast to prostacyclin – iloprost is converted to dinor-and tetranor-iloprost metabolites via beta-oxidation [25]. The liver is known to be a major site of this catabolic pathway, however, recent studies in isolated perfused rabbit lungs demonstrated that the conversion of iloprost to these beta-oxidation products also takes place in the lung tissue itself [26]. …”

Cardiopulmonary effects of iloprost in experimental acute lung injury

“…Moreover, SCHERMULY et al [30] showed that inhaled iloprost rapidly enters the intravascular compartment in healthy isolated rabbit lungs. Therefore, a retarded release of iloprost from out of the alveolar space, which might have contributed to a delayed selective vasodilation in the present study, seems to be improbable.…”