title: Gefitinib (Iressa) inhibits the CYP3A4-mediated formation of 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin but activates that of 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin from irinotecan.
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 (CL(int)) in the presence of 40 microM 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. CL(int) in the presence of 20 microM 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 microM or higher. CL(int) in the presence of 40 microM 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.
authors.affiliation: Department of Clinical Oncology, Saitama Medical School, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan. fujitak@saitama-med.ac.jp
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
authors.forename: Masaru
authors.initials: M
authors.lastname: Narabayashi
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Miya
authors.forename: Fumio
authors.initials: F
authors.lastname: Nagashima
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Kodama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Araki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Endo
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D000077156:Gefitinib; D006801:Humans; D000077146:Irinotecan; D008862:Microsomes, Liver / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: C113402:7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine; D065607:Cytochrome P-450 Enzyme Inhibitors; D011799:Quinazolines; C100720:RPR 121056; D000077146:Irinotecan; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D000077156:Gefitinib; D002166:Camptothecin