title: Animal pharmacokinetics of inogatran, a low-molecular-weight thrombin inhibitor with potential use as an antithrombotic drug.
abstract: Pharmacokinetics, excretion, and metabolism of inogatran, a low-molecular-weight thrombin inhibitor, were studied in the rat, dog, and cynomolgus monkey. After intravenous administration the half-life was short in all three animal species, due to a small volume of distribution and a relatively high clearance. At doses of 0.1-5 mumol kg-1, the mean residence time was about 10 min in the rat, 35 min in the dog, and 20 min in the cynomolgus monkey. The oral bioavailability of inogatran was incomplete, presumably due to a low membrane permeability, and dose dependent. The bioavailability was 4.8% at 20 mumol kg-1 and 32-51% at 500 mumol kg-1 in rats, 14% at 10 mumol kg-1 and 34-44% at 150 mumol kg-1 in dogs, and 2.1% at 1 mumol kg-1 in cynomolgus monkeys. The radioactivity excreted in urine and faeces was predominantly unchanged inogatran. After intravenous administration the percentage of the radioactivity recovered in faeces was about equal to or higher than the urinary recovery, which indicates biliary excretion of inogatran. After oral dosing, most of the dose was excreted in faeces, as expected from the estimates of oral bioavailability. The plasma protein binding of inogatran in rat, dog, and human plasma, was 20-28%. The blood-plasma concentration ratio was 0.39-0.56, indicating limited distribution into red blood cells.
authors.affiliation: Clinical Pharmacology, Clinical Research and Development, Astra Hässle AB, Mölndal, Sweden. ulf.eriksson@hassle.se.astra.com
authors.forename: U G
authors.initials: UG
authors.lastname: Eriksson
authors.forename: L
authors.initials: L
authors.lastname: Renberg
authors.forename: U
authors.initials: U
authors.lastname: Bredberg
authors.forename: A C
authors.initials: AC
authors.lastname: Teger-Nilsson
authors.forename: C G
authors.initials: CG
authors.lastname: Regårdh
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D019540:Area Under Curve; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008970:Molecular Weight; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D000991:Antithrombins; D001798:Blood Proteins; D010880:Piperidines; C099871:inogatran; D005998:Glycine