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First published on November 15, 2006; DOI: 10.1124/dmd.106.012047

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Received for publication July 18, 2006.
Revised November 8, 2006.
Accepted for publication November 10, 2006.

Effects of green tea compounds on irinotecan metabolism

Snezana Mirkov 1, Bernard J Komoroski 2, Jacqueline Ramirez 1, Andrea Yoder Graber 1, Mark J Ratain 1, Stephen C Strom 2, Federico Innocenti 1*

1 University of Chicago 2 University of Pittsburgh

* Address correspondence to: E-mail: finnocen{at}medicine.bsd.uchicago.edu

Abstract

The effects of green tea compounds on the metabolism of irinotecan have never been investigated. We aimed to study whether catechins (EGCG, ECG, EGC, EC) affect the inactivation metabolism of irinotecan into NPC (by CYP3A4) and SN-38 into 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 HPLC. UGT1A1 mRNA levels were measured by real-time PCR. 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 6-{beta}-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.


Key words: drug interactions, enzyme induction, enzyme inhibitors, glucuronidation, hepatocytes, human CYP enzymes, microsomes, UDP glucuronyltransferases


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