PT  - JOURNAL ARTICLE
AU  - Ken-ichi Fujita
AU  - Yuichi Ando
AU  - Masaru Narabayashi
AU  - Toshimichi Miya
AU  - Fumio Nagashima
AU  - Wataru Yamamoto
AU  - Keiji Kodama
AU  - Kazuhiro Araki
AU  - Hisashi Endo
AU  - Yasutsuna Sasaki
TI  - GEFITINIB (IRESSA) INHIBITS THE CYP3A4-MEDIATED FORMATION OF 7-ETHYL-10-(4-AMINO-1-PIPERIDINO)CARBONYLOXYCAMPTOTHECIN BUT ACTIVATES THAT OF 7-ETHYL-10-[4-<em>N</em>-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO]CARBONYLOXYCAMPTOTHECIN FROM IRINOTECAN
AID  - 10.1124/dmd.105.006205
DP  - 2005 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1785--1790
VI  - 33
IP  - 12
4099  - http://dmd.aspetjournals.org/content/33/12/1785.short
4100  - http://dmd.aspetjournals.org/content/33/12/1785.full
SO  - Drug Metab Dispos2005 Dec 01; 33
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics