title: Preclinical pharmacokinetics of the radiomitigator KZ-41 in rats.
abstract: KZ-41, a quinic acid derivative, significantly reduces mortality in a murine model of hematopoietic acute radiation syndrome. The purpose of this study was to evaluate the systemic pharmacokinetics, elimination, and oral bioavailability of KZ-41 in rats. Male Sprague-Dawley rats (n = 6 per group) received a single dose (10 mg/kg) of KZ-41 administered either intravenously via the jugular vein or orally via gavage. In vitro stability was determined using both rat liver microsomes and the bacteria Gluconobacter oxydans. KZ-41 concentrations were determined using LC-MS/MS (liquid chromatography tandom mass spectrometry). Half-life of KZ-41 was ≈3 hr after either intravenous or oral administration. Mean volume of distribution was 3.3 L/kg. Extent of absorption (F) after oral administration was estimated to be ~100%, which was consistent with the finding that KZ-41 was stable to liver microsomal and bacterial degradation. Following intravenous administration, KZ-41 demonstrated a medium clearance and volume of distribution with a terminal half-life of ≈3 hr. KZ-41 was rapidly and completely absorbed (F ≅ 1), which was consistent with the findings that KZ-41 is resistant to presystemic elimination mechanisms (i.e. enteric bacterial degradation and hepatic metabolism). Thus, KZ-41 represents an excellent candidate for further development as an orally available agent for the mitigation of radiation injury.
authors.affiliation: Kronos Science Laboratory Inc., Phoenix, AZ, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Zeng
authors.forename: Karin Emmons
authors.initials: KE
authors.lastname: Thompson
authors.forename: Chaela S
authors.initials: CS
authors.lastname: Presley
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yates
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002853:Chromatography, Liquid; D004355:Drug Stability; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011837:Radiation-Protective Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: C569814:KZ 41 compound; D011837:Radiation-Protective Agents; D011801:Quinic Acid