Oral Bioavailability and Disposition of [14C]Omapatrilat in Healthy Subjects

The objective of this study was to determine the absolute oral bioavailability and disposition of omapatrilat. This singledose, randomized, crossover study of 20 mg intravenous and 50 mg oral [14C]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailabi...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2001-08, Vol.41 (8), p.833-841
Main Authors: Malhotra, Bimal K., Iyer, Ramaswamy A., Soucek, Kathy M., Behr, Douglas, Liao, Wei-chi, Mitroka, James G., Kaul, Sanjeev, Cohen, Marvin B., Knupp, Catherine A.
Format: Article
Language:English
Subjects:
Absorption
Administration, Oral
Adult
Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics
Antihypertensive agents
Area Under Curve
Biological and medical sciences
Biological Availability
Carbon Radioisotopes
Cardiovascular system
Cross-Over Studies
Humans
Male
Medical sciences
Pharmacology. Drug treatments
Pyridines - adverse effects
Pyridines - pharmacokinetics
Thiazepines - adverse effects
Thiazepines - pharmacokinetics
Tissue Distribution
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Summary:The objective of this study was to determine the absolute oral bioavailability and disposition of omapatrilat. This singledose, randomized, crossover study of 20 mg intravenous and 50 mg oral [14C]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailability of omapatrilat, an orally active vasopeptidase inhibitor. Blood samples were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, plasma, urine, and feces was determined by liquid scintillation counting. Urinary excretion of radioactivity averaged 80% and 64% of intravenous and oral doses, respectively; < 1% of oral dose was excreted unchanged in urine. The absolute oral bioavailability of omapatrilat averaged 31%. Total body clearance of omapatrilat (80 L/h) exceeded liver plasma flow. Apparent steady‐state volume of distribution of omapatrilat (21 L/kg) was extremely high compared with total body water. Omapatrilat undergoes substantial presystemic first‐pass metabolism after oral administration. Omapatrilat is eliminated primarily by metabolism, and its metabolites are eliminated primarily in urine. Extrahepatic organs may be involved in the elimination of omapatrilat. Plasma concentrations of omapatrilat exhibit a prolonged terminal elimination phase, which represents elimination from a deep compartment.
ISSN:0091-2700
1552-4604
DOI:10.1177/00912700122010726