Co-administration of irinotecan decreases the plasma concentration of an active metabolite of amrubicin, amrubicinol in rats.
OBJECTIVE
This study examined the pharmacokinetics of irinotecan (CPT-11), active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide (SN-38G) amrubicin (AMR), and active metabolite amrubicinol (AMR-OH) after intravenous administration of this combination therapy in rats.


METHODS
Male Sprague-Dawley rats were treated with 10 mg/kg CPT-11 with 10 mg/kg AMR. AMR, AMR-OH, CPT-11, SN-38 and SN-38G were measured in plasma, bile, and tissues using high-performance liquid chromatography.


RESULTS
Co-administration of CPT-11 resulted in a significant decrease in plasma concentrations and area under the curves (AUC) of AMR-OH compared with treatment with AMR alone. On the other hand, co-administration of AMR resulted in a slight increase in the initial plasma concentration of SN-38; however, there were no differences in AUC values in CPT-11 and SN-38. The cumulative biliary excretion curves of AMR, CPT-11, and their active metabolites were not changed. CPT-11 inhibited the conversion of AMR to AMR-OH in rat cytosolic fractions.


CONCLUSIONS
CPT-11 did not affect the pharmacokinetic of AMR but decreased the plasma concentration of AMR-OH and might affect the formation of AMR-OH from AMR in hepatocytes.
Maeda
Yukiko
Y
Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Hamada
Akinobu
A
Sanematsu
Emiko
E
Sasaki
Ji-ichro
JI
Yokoo
Koji
K
Hira
Asumi
A
Saito
Hideyuki
H
D000818:Animals; D018943:Anthracyclines / Q000097:blood* / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D020719:Glucuronides / Q000097:blood; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D018943:Anthracyclines; D020719:Glucuronides; C116173:amrubicinol; D000077146:Irinotecan; C055866:amrubicin; D002166:Camptothecin