Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice

Epyrifenacil is a novel herbicide that acts as an inhibitor of protoporphyrinogen oxidase (PPO) and produces hepatotoxicity in rodents by inhibiting PPO. Our previous research revealed that the causal substance of hepatotoxicity is S‐3100‐CA, a major metabolite of epyrifenacil, and that human hepatocyte uptake of S‐3100‐CA was significantly lower than rodent one, suggesting less relevant to hepatotoxicity in humans. To clarify the species difference in the uptake of S‐3100‐CA, we focused on organic anion transporting polypeptides (OATPs) and carried out an uptake assay using human, rat, and mouse OATP hepatic isoforms‐expressing 293FT cells. As a result, all the examined OATPs were found to contribute to the S‐3100‐CA uptake, suggesting that the species difference was not due to the differences in selectivity toward OATP isoforms. When [(14)C]epyrifenacil was administered to mice, the liver concentration of S‐3100‐CA was higher in males than in females. Furthermore, when [(14)C]epyrifenacil was administered with OATP inhibitors, the liver/plasma ratio of S‐3100‐CA was significantly decreased by rifampicin, an Oatp1a1/Oatp1a4 inhibitor in mice, but not by digoxin, an Oatp1a4‐specific inhibitor. This result indicates that Oatp1a1, the predominant transporter in male mice, is the main contributor to the hepatic transport of S‐3100‐CA, and consequently to the gender difference. Moreover, we conclude that the species difference in the hepatic uptake of S‐3100‐CA observed in our previous research is not due to differences in the selectivity toward OATP isoforms but rather to the significantly higher expression of OATPs which mediate uptake of S‐3100‐CA in rodents than in humans.