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.

Keywords::

• Quinic acid
• pharmacokinetics
• acute radiation syndrome

Acknowledgements

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. This technology is patent-pending and is owned by the University of Tennessee Research Foundation

Declaration of interest

This project was supported by Award Number R21AI080534 from the National Institute of Allergy and Infectious Diseases. Additional support for this research was from the Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, and the Van Vleet Endowed Professorship (DDM).