title: 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 approximately 3.5 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 approximately 63%). Compared with infused iloprost, significantly more rapid metabolism to dinor- and 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 perfusate-admixed 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 beta-oxidation, and more rapid appearance of dinor- and tetranoriloprost is noted for the inhalative as compared with the intravascular route of iloprost administration.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University, Klinikstrasse 36, D-35392 Giessen, Germany. ralph.schermuly@innere.med.uni-giessen.de
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulz
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Arne
authors.initials: A
authors.lastname: Meidow
authors.forename: Frank
authors.initials: F
authors.lastname: Rose
authors.forename: Axel
authors.initials: A
authors.lastname: Roehl
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Michael
authors.initials: M
authors.lastname: Hildebrand
authors.forename: Julia
authors.initials: J
authors.lastname: Kurz
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Dieter
authors.initials: D
authors.lastname: Walmrath
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D005260:Female; D016285:Iloprost / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008168:Lung / Q000378:metabolism; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011817:Rabbits
chemical_list: D000336:Aerosols; D002021:Buffers; D010975:Platelet Aggregation Inhibitors; D016285:Iloprost