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

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 , 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. 2


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zamboni, WC
Jung, LL
Strychor, S
Joseph, E
Zamboni, BA
Fetterman, SA
Sidone, BJ
Burke, TG
Curran, DPcurran@pitt.eduCURRAN
Eiseman, JLjle9@pitt.eduJLE9
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: 30 Mar 2021 12:56
URI: http://d-scholarship.pitt.edu/id/eprint/18051

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