Cancer Chemotherapy and Pharmacology

, Volume 41, Issue 6, pp 464–468 | Cite as

Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates

  • Susan M. Blaney
  • Chris Takimoto
  • Daryl J. Murry
  • Nancy Kuttesch
  • Cynthia McCully
  • Diane E. Cole
  • Karen Godwin
  • Frank M. Balis
ORIGINAL ARTICLE

Abstract

Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN-38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 l/kg per h, a volume of distribution at steady state (Vdss) of 1.6 ± 0.7 l/kg and a half-life (t1/2) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUCCSF: AUCP) was only 3.5 ± 2.1%. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vdss was 7.1 ± 1.3 l/kg, and the t1/2 was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 ± 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6% of the total SN-38 in plasma. The AUCCSF: AUCP ratio for irinotecan lactone was 14 ± 3%. SN-38 lactone and carboxylate could not be measured (<1.0 nM ) in CSF. The AUCCSF: AUCP ratio for SN-38 lactone was estimated to be ≤ 8%. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUCCSF: AUCP ratio of 32%.

Key words Irinotecan 9-Aminocamptothecin CSF penetration Topotecan 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Susan M. Blaney
    • 1
  • Chris Takimoto
    • 2
  • Daryl J. Murry
    • 1
  • Nancy Kuttesch
    • 1
  • Cynthia McCully
    • 3
  • Diane E. Cole
    • 3
  • Karen Godwin
    • 3
  • Frank M. Balis
    • 3
  1. 1.Texas Children's Cancer Center, 6621 Fannin Street, MC 3-3320, Houston, TX 77030, USA Tel.: +1-713-770-4588; Fax: +1-713-770-4202US
  2. 2.Medicine Branch, Bethesda, National Cancer Institute, MD 20892, USAUS
  3. 3.Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USAUS

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