title: Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse.
abstract: A new water-soluble derivative of camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), did not exhibit potent antitumor activity in vitro against experimental tumor cells. The 50% effective doses of CPT-11 against KB and L1210 cells were 1100 and 5500 ng/ml, respectively. These values were markedly higher than those of camptothecin (CPT, 0.98 and 3.7 ng/ml) or 7-ethyl-10-hydroxycamptothecin (SN-38, 0.37 and 3.6 ng/ml). CPT-11 was found to be converted into SN-38 in mouse serum. In vitro incubation of CPT-11 in mouse serum or tissue homogenate enhanced the growth-inhibitory activity much more than that expected from the concentration of CPT-11. This enhancement of the activity coincided with that expected from the SN-38 concentration in incubated serum or homogenate, though the contribution of CPT-11 could not be refuted. SN-38 is considered to play a major role in the antitumor activity when CPT-11 is incubated in serum or homogenate. The plasma CPT-11 concentration decreased biexponentially after i.v. administration of CPT-11 into mice with a biological half-life of 0.8 to 1.1 h. The area under the plasma CPT-11 concentration-time curve showed dose dependency. The SN-38 concentration decreased for the first 30 min after administration and was then maintained for a few hours at about 0.1 microgram/ml after i.v. administration of 20 and 40 mg/kg of CPT-11 followed by the log-linear terminal phase with a half-life of about 2 h which was independent of the dose. It is suggested that the maintenance of plasma SN-38 concentration might be necessary for it to exhibit antitumor activity in vivo.
authors.affiliation: Yakult Central Institute for Microbiological Research, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kaneda
authors.forename: H
authors.initials: H
authors.lastname: Nagata
authors.forename: T
authors.initials: T
authors.lastname: Furuta
authors.forename: T
authors.initials: T
authors.lastname: Yokokura
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D000077146:Irinotecan; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin