20(S)-Protopanaxatriol Alters the Toxicity Response of Irinotecan Through Affecting the Pharmacokinetics of Irinotecan

The influence of 20(S)-protopanaxatriol (PPT) towards the intestinal toxicity of irinotecan was evaluated in the present study. Seven days oral gavage of 300 mg/kg of PPT significantly increased irinotecan (i.p., 50 mg/kg, 5 day)-induced intestinal toxicity, as demonstrated by the elevated damage of ileum. Detailed reason was elucidated through evaluating the inhibition of PPT towards the glucuronidation activity of SN-38, which is the active metabolite of irinotecan. The results showed that 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5, and 10 uM of PPT inhibited recombinant UGT1A1-catalyzed glucuronidation of SN-38 by - 18.8, 22.1, 41.1, 65.2, 71.9, 85.4, 90.5, and 92.3%, respectively. The activity of human liver microsomes (HLMs)-catalyzed SN-38 glucuronidation was inhibited by 36.5, 46.8, 52.7, 60.9, 73.4, 79.9, 83.9, and 88.7% at 0.1, 0.25, 0.5, 1, 2.5, 5, 10, and 25 uM of PPT. PPT competitively inhibited recombinant UGT1A1 and HLMs-catalyzed SN-38 glucuronidation. All these results indicated that PPT can increase the toxicity of irinotecan through inhibiting the glucuronidation reaction of its active metabolite SN-38.