Pharmacokinetics and toxicokinetics of an orally active tripeptide, IRI-695, in animals.
Pharmacokinetics and toxicokinetics of IRI-695, a tripeptide, were investigated in the rat, rabbit, dog, and monkey. Tissue distribution and excretion of [14C]IRI-695 were determined in the rat. Following a single intravenous (IV) injection, the elimination half-life (t1/2) of IRI-695 in the rabbit, dog, and monkey was similar (about 65 min) and approximately four times that in the rat (15 min). This difference in t1/2 can be attributed to about four times higher clearance of the drug in rats (11.2 mL min-1 kg-1). The volume of distribution (Vss) in these four species, 132-234 mL kg-1, suggested negligible preferential distribution of IRI-695 to body tissue. After a 5 mg kg-1 oral dose, the absolute bioavailability of IRI-695 was 2.0% in rats and 3.1% in dogs. However, systemic drug exposure in the dog was about five to 10 times that in the rat, which is related to the slower clearance of the peptide in the dog. Toxicokinetic studies in the rat and dog indicated linear kinetics and systemic exposure of IRI-695 up to 300 mg kg-1 d-1 oral doses throughout the 28 d toxicity study. Accumulation of the drug after the repeated oral dosing was negligible. After a single 0.10 mg kg-1 [14C]IRI-695 IV injection in rats, almost all of the radioactivity administered was excreted in urine within 24 h postdose.
Adusumalli
V
V
Immunobiology Research Institute, Annandale, NJ 08801, USA.
Corkum
N
N
Jacala
A
A
Mukherjee
T
T
Goodlett
D
D
Crowther
J
J
McConnell
I
I
Goldstein
G
G
D000595:Amino Acid Sequence; D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D002250:Carbon Radioisotopes; D009842:Oligopeptides; C102802:Ac-Arg-Pro-Asp-NH-isobutyl