Journal
FOOD AND CHEMICAL TOXICOLOGY
Volume 47, Issue 8, Pages 1921-1927Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2009.05.003
Keywords
Ochratoxin A; Toxicokinetic population approach; Male and female F344 rats; Age; Plasma; Simulation
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Ochratoxin A (OTA) is a mycotoxin that causes renal tumors in rodents, particularly in male rats. The present work explored the impact of gender and age on OTA toxicokinetics in F344 rats after a single oral dose (0.5 mg/kg b.w.). OTA plasma concentrations were analysed with a validated HPLC-FLD method and a population approach (NONMEM VI) was used to perform the kinetic analysis and the one year exposure simulation (0.21 mg/kg daily). Maximum observed OTA concentration (CMAX(obs)) was at 2 h in all groups except in mature females (6 h). Mature females reached higher CMAX(obs) than males of the same age. Apparent volume of distribution, but not apparent total plasma clearance, increased significantly with body weight (P < 0.01) resulting in the following values for the terminal plasma half life (h) in males: 219 (young), 264 (matures) and females: 191 (young), 205 (matures). In addition mature males showed a significant lower relative bioavailability. The simulation showed similar plasma concentrations in males and females after two-months. Thus, toxicokinetic does not seem to explain sex-differences in toxicity in long-term studies. However, the age and weight should be taken into account in short-term toxicological studies if sex-differences are studied. (C) 2009 Elsevier Ltd. All rights reserved.
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