title: Pharmacokinetic characteristics of the novel anticancer agent CPT-11 and its active metabolite in plasma and lung lymph fluid following intravenous administration to sheep.
abstract: 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11, 100286-90-6) is one of the most promising novel anticancer agents, especially for lung cancer. 7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolic of CPT-11, has much stronger cytotoxicity than CPT-11. The present study was designed to evaluate the distribution and behavior of CPT-11 and SN-38 in lung lymph circulation following intravenous infusion. Awake sheep with chronically instrumented lung lymph fistulas were prepared. The concentrations of CPT-11 and SN-38 in plasma and lung lymph fluid were measured after intravenous infusion of 100 mg/body of CPT-11 for 90 min. SN-38 constantly showed higher lymph to plasma concentration ratios than those of CPT-11, and the % area under the curve (AUC) ratio of SN-38/CPT-11 in lymph fluid was significantly higher than that in plasma. These data indicated that SN-38 distributed in lung tissue moved more easily into lung lymph fluid than CPT-11, and might be more rapidly metabolized in lung tissue than plasma. CPT-11 may have favorable therapeutic effects on intrathoracic malignancies such as lung cancer and lymph metastasis.
authors.affiliation: First Department of Internal Medicine, Shinshu University School of Medicine, Asahi Matsumoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Koizumi
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: M
authors.initials: M
authors.lastname: Hanaoka
authors.forename: T
authors.initials: T
authors.lastname: Miyahara
authors.forename: T
authors.initials: T
authors.lastname: Kaneki
authors.forename: H
authors.initials: H
authors.lastname: Yamamoto
authors.forename: R L
authors.initials: RL
authors.lastname: Ge
authors.forename: K
authors.initials: K
authors.lastname: Fujimoto
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Sekiguchi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008168:Lung / Q000378:metabolism*; D008196:Lymph / Q000378:metabolism*; D012756:Sheep
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin