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Drug Metabolism and Disposition Fast Forward
First published on August 25, 2005; DOI: 10.1124/dmd.105.006205

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Received for publication June 29, 2005.
Revised August 17, 2005.
Accepted for publication August 25, 2005.

Gefitinib (Iressa) inhibits the CYP3A4-mediated formation of NPC, but activates that of APC from irinotecan

Ken-ichi Fujita 1*, Yuichi Ando 1, Masaru Narabayashi 1, Toshimichi Miya 1, Fumio Nagashima 1, Wataru Yamamoto 1, Keiji Kodama 1, Kazuhiro Araki 1, Hisashi Endo 1, Yasutsuna Sasaki 1

1 Saitama Medical School

* Address correspondence to: E-mail: fujitak{at}saitama-med.ac.jp

Abstract

Gefitinib (Iressa) is an anticancer drug that selectively inhibits tyrosine kinases of epidermal growth factor receptor. Gefitinib might affect CYP3A4-mediated metabolism, since the drug is a substrate of human CYP3A. In this study, we evaluated the effects of gefitinib on drug metabolism catalyzed by human CYP3A4. The effects of gefitinib on the CYP3A4-mediated formation of NPC (7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin) and that of APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin) from irinotecan were examined with the use of human liver and small intestinal microsomes. Gefitinib inhibited the formation of NPC in liver and small intestinal microsomes. The apparent intrinsic metabolic clearance (CLint) in the presence of 40 µM gefitinib was equivalent to about 26% of control in liver microsomes and 45% of control in small intestinal microsomes. Gefitinib stimulated the formation of APC by CYP3A4. CLint in the presence of 20 µM gefitinib with human liver microsomes was about 1.9 times higher than control. In human small intestinal microsomes, APC formation was enhanced by the addition of gefitinib at concentrations 20 µM or higher. CLint in the presence of 40 µM gefitinib was 2.8 times higher than control. Thus, we discovered that gefitinib inhibited the formation of NPC, but stimulated the formation of APC from irinotecan.


Key words: CYP inhibition, CYP3A, drug-drug interactions, enzyme kinetics, inhibition, liver microsomes, P450 mechanism


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