Excretion into gastrointestinal tract of irinotecan lactone and carboxylate forms and their pharmacodynamics in rodents.
OBJECTIVE
To investigate the excretion of irinotecan hydrochloride (CPT-11) and its active metabolite, SN-38, into the gastrointestinal lumen via the biliary and/or intestinal membrane route after dosing with lactone and carboxylate forms of CPT-11, and to evaluate the toxic and antitumor effects of the two forms.


METHODS
The excretions of CPT-11 and SN-38 were investigated by the in situ perfusion technique using rats. The incidence of delayed diarrhea was evaluated after i.v. dosing (60 mg/kg) with CPT-11 lactone and carboxylate forms for 4 days. Antitumor activity and changes in body weight were investigated in mice with Meth A tumors.


RESULTS
The excretion of CPT-11 into bile was greater in dosing with CPT-11 carboxylate than that with its lactone form, whereas the exsorption across intestinal membrane was greater in dosing with CPT-11 lactone than that with its carboxylate form. Dosing with CPT-11 lactone dose-dependently inhibited the increase in tumor weights in Meth A tumor mice, whereas the dosing with its carboxylate form reduced the antitumor effect.


CONCLUSIONS
The decreased antitumor effect caused by dosing with the CPT-11 carboxylate form could be due to less accumulation in the tissue including tumor cells resulting from the rapid elimination of the form in the body.
Arimori
K
K
Department of Pharmacy, Miyazaki Medical College, Japan. arimori@fc.miyazaki-med.ac.jp
Kuroki
N
N
Kumamoto
A
A
Tanoue
N
N
Nakano
M
M
Kumazawa
E
E
Tohgo
A
A
Kikuchi
M
M
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D003967:Diarrhea / Q000139:chemically induced; D004064:Digestive System / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D015994:Incidence; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects
D004791:Enzyme Inhibitors; D000077146:Irinotecan; D002166:Camptothecin