title: Gefitinib increases serum concentrations of oral irinotecan and SN-38 without increasing the biliary concentration of SN-38 in rats.
abstract: BACKGROUND
  Gefitinib competes with topoisomerase I inhibitors at drug efflux pumps in vitro. We evaluated the effects of oral gefitinib on pharmacokinetic parameters of orally coadministered irinotecan.
  
  
  METHODS
  We measured the serum pharmacokinetic parameters and biliary excretion of irinotecan, SN-38 and its glucuronide after irinotecan (50 or 100 mg/kg) was orally administered with or without gefitinib 100 mg/kg to rats. We measured the concentrations of irinotecan and SN-38 in the small intestine, liver, lungs and kidneys in each rat.
  
  
  RESULTS
  The plasma area under the curve (0-24 h) of irinotecan and SN-38 was increased significantly, while the apparent elimination constant of irinotecan was decreased significantly. Gefitinib significantly increased the biliary cumulative amounts of irinotecan, but not of SN-38, and also influenced the enterohepatic circulation of irinotecan, but not of SN-38.
  
  
  CONCLUSIONS
  Gefitinib increased the serum concentrations of irinotecan and SN-38 following oral administration of irinotecan without increasing the biliary excretion of SN-38 in vivo.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. yi-nakamu@umin.ac.jp
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kurika
authors.initials: K
authors.lastname: Satake
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sano
authors.forename: Akiko
authors.initials: A
authors.lastname: Ito
authors.forename: Megumi
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ikegami
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakano
authors.forename: Mikio
authors.initials: M
authors.lastname: Oka
authors.forename: Seigo
authors.initials: S
authors.lastname: Sawada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Soda
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D000077156:Gefitinib; D000077146:Irinotecan; D008297:Male; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D011799:Quinazolines; D000077146:Irinotecan; D000077156:Gefitinib; D002166:Camptothecin