Toxicokinetics of citreoviridin<i>in vivo</i>and<i>in vitro</i>

<jats:title>Abstract</jats:title><jats:p>Citreoviridin (CIT) produced by<jats:italic>Penicillium citreonigrum</jats:italic>as a secondary metabolite is a yellow rice toxin that has been reported to be related to acute cardiac beriberi; however, its toxicokinetics remain unclear. The present study elucidated the toxicokinetics through swine<jats:italic>in vivo</jats:italic>experiments and predicted the human toxicokinetics by a comparison with findings from<jats:italic>in vitro</jats:italic>experiments. Swine<jats:italic>in vivo</jats:italic>experiments revealed that CIT had a high bioavailability of more than 90%. In addition, it showed a large volume of distribution (1.005 ± 0.195 L/kg) and long elimination half-life (17.7 ± 3.3 h) in intravenous. These results suggested the possibility of a slow metabolism of CIT. An intestinal permeability study using the human cell line Caco-2 showed that CIT had a high permeability coefficient, suggesting it would be easily absorbed in human intestine, similar to its absorption in swine. The metabolite profiles were investigated by incubating CIT with S9 obtained from swine and humans. Hydroxylation, methylation, desaturation and dihydroxylation derivatives were detected as the predominant metabolites, and CIT glucuronide was produced slowly compared with above metabolites. A comparison of the peak area ratios obtained using quadrupole time-of-flight mass spectrometer showed that the rates of all of the main metabolites except for glucuronide produced using human S9 were three-fold higher than those obtained using swine S9. Furthermore, the elimination of CIT using human S9 was more rapid than when using swine S9, indicating that CIT would be metabolized faster in humans than in swine. These<jats:italic>in vivo</jats:italic>results suggested that CIT is easily absorbed in swine and persists in the body for a long duration. Furthermore, the CIT metabolism appeared to be faster in human liver than in swine liver<jats:italic>in vitro</jats:italic>, although the bioavailability of CIT was predicted to be similarly high in humans as in swine.</jats:p>