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Effect of hesperidin on the pharmacokinetics of CPT‐11 and its active metabolite SN‐38 by regulating hepatic Mrp2 in rats

The usage of irinotecan hydrochloride (CPT‐11) chemotherapy is hindered by its dose‐limiting diarrhea which appears to be associated with the intestinal exposure to SN‐38, the active metabolite of CPT‐11. Hesperidin, a safe and natural food ingredient flavonoid, exhibits various biological properties. Accumulated evidence showed that the regulatory effect of hesperidin on the expression of Mrp2 in the liver may be one of the critical factors controlling the biliary excretion of SN‐38. This study examined the effect of hesperidin on the pharmacokinetics of CPT‐11 and SN‐38 as well as the regulatory effect on the hepatic expression of Mrp2. Compared with the control group, the AUC5‐t was increased to 115% of CPT‐11 and 122% of SN‐38; the CL was decreased to 87% for CPT‐11; the tissue concentration was increased in the liver, kidney and colon; and the accumulated biliary excretion was significantly decreased to 77% for CPT‐11 and 76% for SN‐38 in hesperidin‐treated rats. Furthermore, the expression of Mrp2 in the liver was significantly decreased to 37% in the hesperidin‐treated rats compared with that of the control group. These results indicate that oral administration of hesperidin significantly increased the AUC5‐t and reduced the clearance of CPT‐11 and SN‐38, possibly by decreasing the hepatic expression of Mrp2, and thus inhibiting the biliary excretion of CPT‐11 and SN‐38. The results from this present study suggest that hesperidin may reduce the exposure of CPT‐11 and SN‐38 in the intestine by reducing the amount of biliary excretion of CPT‐11 and SN‐38. Copyright © 2016 John Wiley & Sons, Ltd.