A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort

Hu, Ze-Ping, Yang, Xiao-Xia, Chen, Xiao, Cao, Jie, Chan, Eli, Duan, Wei, Huang, Min, Yu, Xue-Qing, Wen, Jing-Yuan and Zhou, Shu-Feng (2007) A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort. Current Drug Metabolism, 8 2: 157-171. doi:10.2174/138920007779815995

Author Hu, Ze-Ping
Yang, Xiao-Xia
Chen, Xiao
Cao, Jie
Chan, Eli
Duan, Wei
Huang, Min
Yu, Xue-Qing
Wen, Jing-Yuan
Zhou, Shu-Feng
Title A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort
Journal name Current Drug Metabolism   Check publisher's open access policy
ISSN 1389-2002
Publication date 2007-02
Sub-type Critical review of research, literature review, critical commentary
DOI 10.2174/138920007779815995
Volume 8
Issue 2
Start page 157
End page 171
Total pages 15
Place of publication Bussum, The Netherlands
Publisher Bentham Science Publishers
Language eng
Abstract 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-II and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-tenn (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 (hyperform, 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 (C-0) of CPT-11, the area under the concentration-time curve (AUC0-10hr and maximum plasma concentration (C-max) of SN-38. The ethanolic extracts (EE) of SJW at 5 mu 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 mu g/ml, SJW EE at 5 mu g/ml, and quercetin at 10 mu M significantly increased the glucuronidation of SN-38 in H4-II-E cells. A 2-hr pre-incubation of quercetin (100 mu M) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1 mu 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-I I 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.
Keyword Biochemistry & Molecular Biology
Pharmacology & Pharmacy
irinotecan (CPT-11)
St. John's wort
Rat Hepatoma-cells
Camptothecin Derivative Irinotecan
Biliary-excretion Mechanisms
Metastatic Colorectal-cancer
Organic Anion Transporter
Delayed-onset Diarrhea
Human Topoisomerase-i
Clinical Pharmacokinetics
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes This document is a journal review.

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Faculty of Health and Behavioural Sciences -- Publications
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Created: Mon, 18 Feb 2008, 16:29:42 EST