A mechanistic study on altered pharmacokinetics of irinotecan by St. Johns wort

Hu, Ze-Ping, Yang, Xiao-Xia, Chen, Xiao, Chan, Eli, Duan, Wei, Huang, Min, Yu, Xue-Qing, Wen, Jing-Yuan, Zhou, Shu-Feng and Cao, Jie 2007, A mechanistic study on altered pharmacokinetics of irinotecan by St. Johns wort, Current drug metabolism, vol. 8, no. 2, pp. 157-171.


Title A mechanistic study on altered pharmacokinetics of irinotecan by St. Johns wort
Author(s) Hu, Ze-Ping
Yang, Xiao-Xia
Chen, Xiao
Chan, Eli
Duan, Wei
Huang, Min
Yu, Xue-Qing
Wen, Jing-Yuan
Zhou, Shu-Feng
Cao, Jie
Journal name Current drug metabolism
Volume number 8
Issue number 2
Start page 157
End page 171
Publisher Bentham Science Publishers Ltd.
Place of publication Hilversum, The Netherlands
Publication date 2007-02
ISSN 1389-2002
1875-5453
Keyword(s) rrinotecan (CPT-11)
SN-38
St. John's wort
hyperforin
hypericin
metabolism
transport
pharmacokinetics
Summary Irinotecan (CPT-11) is an important anticancer drug in management of advanced colon cancer. A marked protective effect on CPT-11-induced blood and gastrointestinal toxicity is obtained by combination of St. John's wort (SJW) in recent clinical and rat studies. However, the mechanism is unclear. This study aimed to explore the effects of SJW on the pharmacokinetics of CPT-11 and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-term (3 days) and long-term (14 days) pretreatment with SJW were conducted in rats to examine the effects of co-administered SJW on the plasma pharmacokinetics of CPT-11, SN-38 and SN- 38 glucuronide. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were utilized to study the effects of aqueous and ethanolic extracts (AE and EE) and major active components (hyperforin, hypericin and quercetin) of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation. Co-administered SJW for consecutive 14 days significantly decreased the initial plasma concentration (C0) of CPT-11, the area under the concentration-time curve (AUC0-10hr) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 μ g/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 g/ml, SJW EE at 5 μg/ml, and quercetin at 10μ M significantly increased the glucuronidation of SN-38 in H4- II-E cells. A 2-hr pre-incubation of quercetin (100μ M) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1μ M) significantly decreased the intracellular accumulation of CPT-11. In addition, pre-incubation of hypericin, SJW EE and quercetin significantly increased the intracellular accumulation of SN-38. Aqueous and ethanolic SJW extracts and its major active components did not alter the plasma protein binding of CPT-11 and SN-38. These results indicated that the aqueous and ethanolic extracts of SJW and its major active components could markedly alter glucuronidation of SN-38 and intracellular accumulation of CPT-11 and SN-38, which probably provides partial explanation for the altered plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing effects on the toxicities of CPT-11. Further studies are needed to explore the role of both pharmacokinetic and pharmacodynamic components in the protective effect of SJW against the toxicities of CPT-11.
Language eng
Field of Research 110404 Traditional Chinese Medicine and Treatments
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2007, Bentham Science Publishers Ltd.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30007441

Document type: Journal Article
Collection: School of Medicine
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 17 times in TR Web of Science
Scopus Citation Count Cited 17 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 565 Abstract Views  -  Detailed Statistics
Created: Mon, 29 Sep 2008, 08:52:09 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.