Involvement of UDP-glucuronosyltransferase activity in irinotecan-induced delayed-onset diarrhea in rats
| 详细信息 | 推荐本文 | |
- 作者：Masaharu Onoue ; Akinobu Kurita ; Shoichi Kado ; Tsuneo Matsumoto ; Norimasa Kaneda ; Kazumi Uchida ; Ikuo Kato and Teruo Yokokura
- 关键词：Irinotecan hydrochloride ; CPT ; 11 ; Diarrhea ; Gunn rat ; UDP ; glucuronosyltransferase
- 刊名：Cancer Chemotherapy and Pharmacology
- 出版时间：April, 2008
- 出版年：2008
- 期刊代码：24_0344-5704
- 类别：med
- 卷：61
- 期：4
- 页码：595-605
- 数据来源：sp
摘要
We assessed the involvement of UDP-glucuronosyltransferase (UGT) activity in episodes of irinotecan hydrochloride (CPT-11)-induced delayed-onset diarrhea using a mutant rat strain with an inherited deficiency of UGT1A (Gunn rats). Gunn rats exhibited severe diarrhea after the intravenous administration of CPT-11 at a dose of 20 mg/kg, whereas Wistar rats did not. In the epithelium of the small intestine and cecum in Gunn rats, the shortening of villi, degeneration of crypts, and destruction of the nucleus were observed. The AUC, MRT, and t 1/2 of CPT-11, and the AUC of 7-ethyl-10-hydroxycamptothecin (SN-38) in plasma were, respectively, 1.6-fold, 1.5-fold, 1.7-fold, and 6.5-fold higher, and the cumulative biliary excretion rate of SN-38 was 2.3-fold higher, in Gunn rats than Wistar rats. SN-38 glucuronide excreted via bile in Wistar rats was not de-conjugated in the small intestinal lumen. The SN-38 AUC values in small intestinal tissues were also 5.0 to 5.8-fold higher in Gunn rats than Wistar rats. In conclusion, Gunn rats developed severe delayed-onset diarrhea after i.v. administration of CPT-11 at a much lower dose. Severe intestinal impairments would be induced in Gunn rats through exposure to SN-38 at high levels for a long period mainly via the intestinal lumen and partially via the bloodstream. These results clarified that the deficiency of UGT activity contributed greatly to the induction of the CPT-11-induced delayed-onset diarrhea and epithelial impairment in the intestine. In the clinic, great care is needed when using chemotherapy with CPT-11 in patients with poor UGT activity.