Zamboni, WC and Jung, LL and Strychor, S and Joseph, E and Zamboni, BA and Fetterman, SA and Sidone, BJ and Burke, TG and Curran, DP and Eiseman, JL
(2008)
Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.
Investigational New Drugs, 26 (5).
399 - 406.
ISSN 0167-6997
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Abstract
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/m 2, 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. © 2007 Springer Science+Business Media, LLC.
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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
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Zamboni, WC | | | | Jung, LL | | | | Strychor, S | | | | Joseph, E | | | | Zamboni, BA | | | | Fetterman, SA | | | | Sidone, BJ | | | | Burke, TG | | | | Curran, DP | curran@pitt.edu | CURRAN | | Eiseman, JL | jle9@pitt.edu | JLE9 | |
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Date: |
1 October 2008 |
Date Type: |
Publication |
Journal or Publication Title: |
Investigational New Drugs |
Volume: |
26 |
Number: |
5 |
Page Range: |
399 - 406 |
DOI or Unique Handle: |
10.1007/s10637-007-9109-9 |
Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
Refereed: |
Yes |
ISSN: |
0167-6997 |
MeSH Headings: |
Animals; Camptothecin--analogs & derivatives; Camptothecin--pharmacokinetics; Female; Half-Life; Hydroxy Acids--blood; Lactones--blood; Liposomes--pharmacokinetics; Mice; Mice, SCID; Organosilicon Compounds--pharmacokinetics; Spleen--metabolism; Tissue Distribution |
PubMed ID: |
18246299 |
Date Deposited: |
08 Apr 2013 17:29 |
Last Modified: |
12 Jun 2021 22:56 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/18051 |
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