Characterization of secretory intestinal transport of the lactone form of CPT-11.
OBJECTIVE
It has been reported that a significant portion of the lactone form of 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin (CPT-11) is excreted into the gastrointestinal lumen via the intestinal membrane and that carboxylesterase activity, which converts CPT-11 to SN-38, was detected in the intestine. It is possible that a reduction in the excretion of CPT-11 lactone into the gastrointestinal lumen induces the gastrointestinal toxicity. The purpose of this study was to investigate the characteristics of transporter(s) that contribute to the jejunal efflux of the lactone form of CPT-11.


METHODS
The serosal-to-mucosal permeation rate of CPT-11 lactone was investigated in everted sac studies.


RESULTS
The secretory transport required metabolic energy and was diminished by sulfobromophthalein (BSP) and 1-naphthol, inhibitors of the ME3277 transport system. However, inhibitors of breast cancer resistance protein (Bcrp), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) did not affect the secretion of CPT-11 lactone.


CONCLUSIONS
The results suggest that a specific transport system, which is identical to the ME3277 transport system, plays a major role in the secretion of CPT-11 lactone.
Department of Pharmacy, Sapporo Social Insurance General Hospital, Sapporo, 004-8618, Japan.
Isao
I
Takemoto
Shirou
S
Itagaki
Makoto
M
Chiba
Tatsuya
T
Itoh
Takeshi
T
Hirano
Ken
K
Iseki
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics*; D001693:Biological Transport, Active; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D000077146:Irinotecan; D007583:Jejunum / Q000378:metabolism*; D007783:Lactones; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D000077146:Irinotecan; D002166:Camptothecin