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.

The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism

“…Thus, our group is engaged in the identification of novel targets and therapeutic options designed to protect RECs from environmental stress. Toward this end, we have discovered a new class of orally bioavailable quinic acid (QA) analogs [ 13 ], which counteract p38 MAPK-dependent pro-apoptotic signaling in human RECs exposed to genotoxic stress including radiation and melphalan [ 14 , 15 ].…”

Small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities inHypmice

“…We contracted the in vitro ADME screening and in vivo PK studies with Eurofins Pharma Discovery Services. Microsomal stability of ZINC13407541 and ZINC13407541 analogues was determined in liver microsomes, including human liver microsomes (HLM) and mouse liver microsomes (MLM) to determine potential species differences in metabolism (42) . Aqueous solubility was assessed in PBS (pH 7.4), simulated intestinal fluid, and simulated gastric fluid.…”

Discoveries of Targets and Novel Agents for the Treatment of Ischemic Retinopathy and Neovascular Disease

“…Murine ocular pharmacokinetics of KZ-41 delivered topically to the mouse eye was characterized for penetration into ocular tissues using analytical methods described previously [166,167]. Adult C57BL/6J mice received a single ocular administration of KZ-41-loaded NE (100 mg/kg) to the right eye; the left eye was dosed with vehicle for contralateral controls.…”

“…Pharmacokinetic studies were performed as previously described [166,167,253,254]. Animals will receive either a single intravenous or oral dose of JP-153 (5, 10 mg/kg, respectively).…”

“…JP-153 (1 µM) was assessed in pooled liver microsomes from human, mouse, and rats [166]. Briefly, JP-153 was incubated in duplicate with microsomes at 37°C.…”