Metabolism and toxicokinetics of the mycotoxin ochratoxin A in F344 rats

Abstract

Male (n=18) and female (n=18) F344 rats were administered a single dose of OTA (0.5 mg/kg b.w.) in corn oil by gavage. Animals (n=3) were sacrificed 24, 48, 72, 96, 672 and 1,344 hours after OTA administration and concentrations of OTA and OTA-metabolites in urine, feces, blood, liver and kidney were determined by HPLC with fluorescence detection and/or by LC-MS/MS. Recovery of unchanged OTA in urine amounted to 2.1% of dose in males and 5.2% in females within 96 h. In feces, only 5.5% resp. 1.5% of dose were recovered. The major metabolite detected was OTalpha, low concentrations of OTA-glucosides were also present in urine. Other postulated metabolites were not observed. The maximal blood levels of OTA were observed between 24 and 48h after administration and were app. 4.6 µmol/l in males and 6.0 µmol/l in females. Elimination of OTA from blood followed first-order kinetics with a half-life of app. 230h calculated from 48h to 1344h. In liver of both male and female rats OTA-concentrations were less than 12 pmol/g tissue, with a maximum at 24h after administration. In contrast, OTA accumulated in the kidneys, reaching a concentration of 480 pmol/g tissue in males 24h after OTA-administration. In general, tissue concentrations in males were higher than in females. OTalpha was not detected in liver and kidney tissue of rats administered OTA and OTalpha concentrations in blood were low (10-15 nmol/1). The high concentrations of OTA in kidneys of male rats may explain the organ- and gender-specific toxicity of OTA.