Biliary excretion of irinotecan and its metabolites.
OBJECTIVE
The aim of this study was to investigate the excretion of irinotecan hydrochloride (CPT-11) and its metabolites into the gastrointestinal lumen via the biliary route after intravenous administration of lactone and carboxylate forms of CPT-11.


METHODS
Biliary excretions of CPT-11 and its metabolites, SN-38 and SN-38-glucuronide, were investigated by an in vivo administration study using rats. The biliary excretion profiles for both the lactone and carboxylate forms of CPT-11 and its metabolites were determined.


RESULTS
After the i.v. injection of the lactone form of CPT-11, the cumulative biliary excretion of SN-38-glucuronide was much greater than that of CPT-11 and SN-38, and biliary excretion of SN-38 was less than that of CPT-11. Further, CPT-11 and SN-38 were mainly excreted into bile as carboxylate forms. After the administration of the CPT-11 carboxylate form, biliary excretion of SN-38-glucuronide was significantly smaller than that after the administration of CPT-11 lactone form. On the other hand, biliary excretion of CPT-11 and SN-38 was greater after dosing with the CPT-11 carboxylate form than that after the CPT-11 lactone form.


CONCLUSIONS
The results suggest that the rate of conversion of lactone to carboxylate forms of CPT-11 and its metabolites plays a major role in the biliary excretion of these compounds.
Itoh
Tatsuya
T
Department of Pharmacy, Sapporo Social Insurance General Hospital, Chuo-2-jo, 6-chome, Atsubetsu-ku, Sapporo, Japan.
Takemoto
Isao
I
Itagaki
Shirou
S
Sasaki
Kentaro
K
Hirano
Takeshi
T
Iseki
Ken
K
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics*; D001659:Biliary Tract / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D002264:Carboxylic Acids / Q000737:chemistry; D020719:Glucuronides / Q000493:pharmacokinetics*; D000077146:Irinotecan; D007783:Lactones / Q000737:chemistry; D008297:Male; D051381:Rats; D017208:Rats, Wistar
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D002264:Carboxylic Acids; D020719:Glucuronides; D007783:Lactones; D000077146:Irinotecan; D002166:Camptothecin