Preclinical pharmacokinetics of the radiomitigator KZ-41 in rats

Kui Zeng, Karin Emmons Thompson, Chaela S. Presley, Duane Miller, Charles Yates

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 (10mg/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 ≈3hr after either intravenous or oral administration. Mean volume of distribution was 3.3L/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 ≈3hr. 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.

Original languageEnglish (US)
Pages (from-to)1006-1012
Number of pages7
JournalXenobiotica
Volume41
Issue number11
DOIs
StatePublished - Nov 1 2011

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Pharmacokinetics
Intravenous Administration
Oral Administration
Half-Life
Rats
Acute Radiation Syndrome
Gluconobacter oxydans
Quinic Acid
Liver
Radiation Injuries
Jugular Veins
Liver Microsomes
Liquid Chromatography
Biological Availability
Sprague Dawley Rats
Radiation
Degradation
Mass Spectrometry
Liquid chromatography
Bacteria

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Toxicology
  • Biochemistry
  • Health, Toxicology and Mutagenesis

Cite this

Preclinical pharmacokinetics of the radiomitigator KZ-41 in rats. / Zeng, Kui; Thompson, Karin Emmons; Presley, Chaela S.; Miller, Duane; Yates, Charles.

In: Xenobiotica, Vol. 41, No. 11, 01.11.2011, p. 1006-1012.

Research output: Contribution to journalArticle

Zeng, Kui ; Thompson, Karin Emmons ; Presley, Chaela S. ; Miller, Duane ; Yates, Charles. / Preclinical pharmacokinetics of the radiomitigator KZ-41 in rats. In: Xenobiotica. 2011 ; Vol. 41, No. 11. pp. 1006-1012.
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