title: Disposition of irinotecan and SN-38 following oral and intravenous irinotecan dosing in mice.
abstract: The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38 lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1 l/m2. After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 +/- 0.67%, whereas at 100 ng/ml the percent unbound was 1.18 +/- 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present study provide important information for the design of phase I studies of oral irinotecan.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38101-0318, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
authors.forename: W C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: W R
authors.initials: WR
authors.lastname: Crom
authors.forename: P J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D007275:Injections, Intravenous; D000077146:Irinotecan; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009447:Neuroblastoma; D011485:Protein Binding
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001798:Blood Proteins; D000077146:Irinotecan; D002166:Camptothecin