Disposition of irinotecan and SN-38 following oral and intravenous irinotecan dosing in mice |
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Authors: | Clinton F Stewart William C Zamboni William R Crom Peter J Houghton |
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Institution: | (1) Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38101-0318, USA Tel. 901-495-3663; Fax 901-525-6869, US;(2) Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN, USA, US;(3) The Center for Pediatric Pharmacokinetics and Therapeutics, University of Tennessee, Memphis, TN, USA, US;(4) Department of Pharmacology, University of Tennessee, Memphis, TN, USA, US |
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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.
Received: 30 August 1996 / Accepted: 27 November 1996 |
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Keywords: | Irinotecan SN-38 Pharmacokinetics |
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