title: Effective irinotecan (CPT-11)-containing liposomes: intraliposomal conversion to the active metabolite SN-38.
abstract: Irinotecan hydrochloride (CPT-11) is a prodrug of SN-38, which is an active metabolite with antitumor activity and side toxicity. The activities of CPT-11 and SN-38 depend on the closed lactone ring form of SN-38. We have examined the tissue distributions of the closed and open forms of CPT-11 and SN-38 in Lewis lung carcinoma-bearing mice after the administration of liposomal CPT-11 (S-Lip) and polyethyleneglycol (PEG)-modified S-Lip (S-PEG). The plasma concentrations of closed CPT-11 and SN-38 were increased by liposomalization, and their blood circulation was prolonged by the PEG modification. The concentrations of closed CPT-11 and SN-38 in tumors were elevated by both the liposomalization and PEG modification. The closed/total ratio of SN-38 in the tumors of the S-PEG group was greater than that of the CPT-11 solution (Sol) group. Thus, SN-38 was thought to be generated in intact liposomes containing CPT-11. The bile concentration of closed SN-38, which is responsible for CPT-11-induced intestinal disorder, was decreased by liposomalization. In an in vitro experiment, the SN-38/CPT-11 ratio in the tumor cells of the S-Lip group was found to be higher than that of the Sol group, and the ratio of the closed form of SN-38 was increased by the liposomalization. Laser scanning confocal microscopy showed the generation of SN-38 in the liposomal membrane after the incubation of S-Lip with carboxylesterase. It is therefore considered that a part of CPT-11 is converted to SN-38 in the intact liposomes.
authors: School of Pharmaceutical Sciences, University of Shizuoka. sadzuka@ys7.u-shizuoka-ken.ac.jp
authors: Y
authors: Y
authors: Sadzuka
authors: S
authors: S
authors: Hirotsu
authors: S
authors: S
authors: Hirota
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001711:Biotransformation; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D004337:Drug Carriers; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D051379:Mice; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008081:Liposomes; D000077146:Irinotecan; D002166:Camptothecin