Abstract
The effects of green tea compounds on the metabolism of irinotecan have never been investigated. We aimed to study whether catechins [(–)-epigallocatechin gallate (EGCG), (–)-epicatechin gallate (ECG), (–)-epigallocatechin (EGC), (–)-epicatechin] affect the inactivation metabolism of irinotecan into 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecin (NPC) (by CYP3A4) and 7-ethyl-10-hydroxycamptothecin (SN-38) into 7-ethyl-10-hydroxycamptothecin glucuronide (SN-38G) (by UGT1A1). Human liver microsomes, hepatocytes and Hep G2 cells were incubated with catechins and treated with irinotecan and/or SN-38. NPC and SN-38G formation was measured by high-performance liquid chromatography. UGT1A1 mRNA levels were measured by real-time polymerase chain reaction. In human liver microsomes, a concentration-dependent decrease in the formation of NPC and SN-38G was observed. In human hepatocytes, a significant increase in SN-38G production was observed in 33% (EGCG), 44% (ECG), and 44% (EGC) of the hepatocyte preparations. Phenobarbital increased the formation of SN-38G in 100% of the same hepatocyte preparations. In Hep G2 cells, no increase in SN-38G formation was observed. With the exception of ECG in one liver, catechins did not increase UGT1A1 mRNA levels. NPC production was also significantly increased in 40% of the hepatocyte preparations for each catechin. However, the production of 6β-hydroxytestosterone remained unaffected in other hepatocyte preparations. At pharmacologically relevant concentrations, catechins are unlikely to inhibit the formation of irinotecan inactive metabolites when administered concomitantly. The induction effect of catechins on UGT1A1 seems to be modest and highly variable. Catechins do not induce CYP3A4 activity. The effect of acute and prolonged use of green tea on the pharmacokinetics of irinotecan in patients remains to be evaluated.
Footnotes
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This work was supported by the University of Chicago Cancer Research Center via the Innovative Cancer Complementary and Alternative Medicine Initiative in Cancer Centers Award [NCI P30 CA14599-27S1 (8/1/01–3/31/02)–Innocenti F. (Project P.I.)]. The funded project was entitled “Modulation of Irinotecan Metabolism and Disposition by Green Tea and Soy Extracts.”
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Preliminary data were presented at the American Society for Clinical Pharmacology and Therapeutics 2004 Annual Meeting, March 24–27, 2004, Miami Beach, FL.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.012047.
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ABBREVIATIONS: EGCG, (–)-epigallocatechin gallate; ECG, (–)-epicatechin gallate; EC, (–)-epicatechin; EGC, (–)-epigallocatechin; SN-38, 7-ethyl-10-hydroxycamptothecin; SN-38G, SN-38-glucuronide; UGT, UDP-glucuronosyltransferase; P450, cytochrome P450; NPC, 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecin; CPT, camptothecin; HMM, hepatocyte maintenance medium; HMM+, serum-free HMM; PCR, polymerase chain reaction; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide.
- Received July 17, 2006.
- Accepted November 10, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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