Influence of sex in ochratoxin a kinetics in f344 rats

Résumé

Ochratoxin A (OTA) is a potent nephrotoxin in all animal species. However, it is especially carcinogenic in male rats, and the mechanism underlying this different sensitivity to OTA toxicity is still unknown. The objective of this study was to explore the impact of sex on OTA kinetics in F344 rats. For this purpose an HPLC-FLD method has been specifically validated for the determination of OTA in plasma, kidney and liver of rats. Several kinetic studies (0.5 mg/kg b.w) have been performed taking into account sex-related factors such as age, food consumption and the male rat-specific protein, á2u-globulin. Data was fit simultaneously using the population approach with NONMEM program. The models that best fit to data were the ones that considered a first order absorption, two compartment disposition model, a distribution of OTA to kidney and liver from the central compartment and an elimination from the liver compartment. Adult males showed a significantly different plasma kinetic profile than females and young males in fed conditions. This could be explained by the significant influence of weight on the apparent volume of distribution and the influence of food on OTA bioavailability only in adult male rats. In spite of the aforementioned, OTA plasma levels estimated after one year exposure simulation (0.21 mg/kg b.w.) were very similar between both sexes. OTA concentrations in kidney and liver were similar in both organs and parallel to plasma concentration in all groups under different dosage regimen.