Wang Xingdong, Rao Zhi, Qin Hongyan, Zhang Guoqiang, Ma Yanrong, Jin Yongwen, Han Miao, Shi Axi, Wang Yanping, Wu Xinan
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, 730000, PR China.
College of Pharmaceutical Sience, Lanzhou University, Lanzhou, 730000, PR China.
Biopharm Drug Dispos. 2016 Oct;37(7):421-432. doi: 10.1002/bdd.2024. Epub 2016 Sep 15.
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 AUC 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 AUC 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.
盐酸伊立替康（CPT - 11）化疗的应用因剂量限制性腹泻而受到阻碍，这种腹泻似乎与肠道接触CPT - 11的活性代谢产物SN - 38有关。橙皮苷是一种安全的天然食品成分类黄酮，具有多种生物学特性。越来越多的证据表明，橙皮苷对肝脏中Mrp2表达的调节作用可能是控制SN - 38胆汁排泄的关键因素之一。本研究考察了橙皮苷对CPT - 11和SN - 38药代动力学的影响以及对肝脏中Mrp2表达的调节作用。与对照组相比，橙皮苷处理的大鼠中，CPT - 11的AUC增加至115%，SN - 38的AUC增加至122%；CPT - 11的CL降低至87%；肝脏、肾脏和结肠中的组织浓度增加；CPT - 11的累积胆汁排泄显著降低至77%，SN - 38的累积胆汁排泄显著降低至76%。此外，与对照组相比，橙皮苷处理的大鼠肝脏中Mrp2的表达显著降低至37%。这些结果表明，口服橙皮苷可显著增加CPT - 11和SN - 38的AUC并降低其清除率，可能是通过降低肝脏中Mrp2的表达，从而抑制CPT - 11和SN - 38的胆汁排泄。本研究结果表明，橙皮苷可能通过减少CPT - 11和SN - 38的胆汁排泄量来降低其在肠道中的暴露。版权所有© 2016约翰威立父子有限公司。
