Investigational New Drugs

, Volume 26, Issue 5, pp 399–406 | Cite as

Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice

  • William C. Zamboni
  • Laura L. Jung
  • Sandra Strychor
  • Erin Joseph
  • Beth A. Zamboni
  • Sarah A. Fetterman
  • Brian J. Sidone
  • Thomas G. Burke
  • Dennis P. Curran
  • Julie L. Eiseman
PHASE II STUDIES

Summary

Purpose: DB-67 is a silatecan, 7-silyl-modified camptothecin, with enhanced lipophilicity and increased blood stability of the active-lactone ring. The generation of a liposomal formulation of DB-67 may be an attractive method of intravenous (IV) administration and may maintain DB-67 in the active-lactone form. We evaluated the tissue and plasma disposition of DB-67 lactone and hydroxy acid after administration of non-liposomal (NL) and liposomal (L) DB-67 in severe combined immunodeficient (SCID) mice. Methods: NL-DB-67 and L-DB-67 10 mg/kg IV × 1 were administered via a tail vein in SCID mice. After dosing, mice (n = 3 per time point) were euthanized and blood (∼1 ml) and tissue were collected from 5 min to 48 h after administration. DB-67 lactone and hydroxy acid concentrations in plasma and DB-67 total (sum of lactone and hydroxyl acid) concentrations in tissues were determined by high-performance liquid chromatography (HPLC) with fluorescence detection. Results: Clearance of DB-67 lactone after administration of NL-DB-67 and L-DB-67 were 1.6 and 3.5 l/h/m2, respectively; DB-67 lactone half-lives after administration of NL-DB-67 and L-DB-67 were 1.4 and 0.9 h, respectively. The percentages of DB-67 lactone in plasma after administration of NL-DB-67 and L-DB-67 were 92% and 89%, respectively. Liver, kidney, spleen, and lung tissues had longer exposure times to DB-67 after administration of L-DB-67 compared with NL-DB-67. Conclusion: In plasma, the majority of DB-67 remained in the lactone form after administration of NL-DB-67 and L-DB-67. The plasma disposition of DB-67 was similar after administration of NL-DB-67 and L-DB-67, suggesting that most of the DB-67 is immediately released from the L-DB-67 formulation. Following administration of L-DB-67, the higher and longer exposure of DB-67 in the spleen, as compared with NL-DB-67, is consistent with splenic clearance of liposomes by the reticuloendothelial system.

Keywords

DB-67 Silatecans Liposomes Pharmacokinetics Camptothecins 

Notes

Acknowledgements

The study was funded by STTR Grant R41 CA91700. We gratefully acknowledge Jeremy Hedges for his assistance in the submission of the manuscript.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • William C. Zamboni
    • 1
    • 2
    • 3
    • 4
    • 9
  • Laura L. Jung
    • 3
  • Sandra Strychor
    • 3
  • Erin Joseph
    • 3
  • Beth A. Zamboni
    • 5
  • Sarah A. Fetterman
    • 3
  • Brian J. Sidone
    • 3
  • Thomas G. Burke
    • 6
  • Dennis P. Curran
    • 7
  • Julie L. Eiseman
    • 3
    • 8
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyUniversity of PittsburghPittsburghUSA
  2. 2.Division of Hematology–Oncology, Department of Medicine, School of MedicineUniversity of PittsburghPittsburghUSA
  3. 3.Molecular Therapeutics Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  4. 4.Department of Obstetrics, Gynecology, and Women’s Health, School of MedicineUniversity of PittsburghPittsburghUSA
  5. 5.Department of MathematicsCarlow UniversityPittsburghUSA
  6. 6.Experimental Therapeutics Program, Markey Cancer Center, Colleges of Pharmacy and MedicineUniversity of KentuckyLexingtonUSA
  7. 7.Department of ChemistryUniversity of PittsburghPittsburghUSA
  8. 8.Department of Pharmacology, School of MedicineUniversity of PittsburghPittsburghUSA
  9. 9.Hillman Cancer Research CenterUniversity of Pittsburgh Cancer InstitutePittsburghUSA

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