PHARMACOKINETICS AND TOXICOKINETICS OF AN ORALLY-ACTIVE TRIPEPTIDE, IRI-695, IN ANIMALS

Pharmacokinetics and toxicokinetics of IRI-695, a tripeptide, were inv estigated in the rat, rabbit, dog, and monkey. Tissue distribution and excretion of [C-14]IRI-695 were determined in the rat. Following a si ngle intravenous (IV) injection, the elimination half-life (t(1/2)) 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 t(1/2) 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 (V-s s) in these four species, 132-234 mL kg(-1), suggested negligible pref erential distribution of IRI-695 to body tissue. After a 5 mg kg(-1) o ral 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 fi ve to 10 times that in the rat, which is related to the slower clearan ce 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. Accumul ation of the drug after the repeated oral dosing was negligible. After a single 0.10 mg kg(-1) [C-14]IRI-695 TV injection in rats, almost al l of the radioactivity administered was excreted in urine within 24 h postdose.