Gefitinib increases serum concentrations of oral irinotecan and SN-38 without increasing the biliary concentration of SN-38 in rats.
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.
Nakamura
Yoichi
Y
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. yi-nakamu@umin.ac.jp
Satake
Kurika
K
Sano
Kazumi
K
Ito
Akiko
A
Yoshikawa
Megumi
M
Ikegami
Yoji
Y
Yoshida
Hisahiro
H
Nakano
Hirofumi
H
Oka
Mikio
M
Sawada
Seigo
S
Soda
Hiroshi
H
Kohno
Shigeru
S
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
D011799:Quinazolines; D000077146:Irinotecan; D000077156:Gefitinib; D002166:Camptothecin