Document Detail


Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.
MedLine Citation:
PMID:  18246299     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 x 1 were administered via a tail vein in SCID mice. After dosing, mice (n = 3 per time point) were euthanized and blood ( approximately 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.
Authors:
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-02-02
Journal Detail:
Title:  Investigational new drugs     Volume:  26     ISSN:  0167-6997     ISO Abbreviation:  Invest New Drugs     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-08-20     Completed Date:  2009-01-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  399-406     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA. zamboniwc@msx.upmc.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Camptothecin / analogs & derivatives*,  pharmacokinetics
Female
Half-Life
Hydroxy Acids / blood
Lactones / blood
Liposomes / pharmacokinetics*
Mice
Mice, SCID
Organosilicon Compounds / pharmacokinetics*
Spleen / metabolism
Tissue Distribution
Grant Support
ID/Acronym/Agency:
R41 CA91700/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/7-tert-butyldimethylsilyl-10-hydroxycamptothecin; 0/Hydroxy Acids; 0/Lactones; 0/Liposomes; 0/Organosilicon Compounds; 7689-03-4/Camptothecin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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