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.