title: Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA. zamboniwc@msx.upmc.edu
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: Laura L
authors.initials: LL
authors.lastname: Jung
authors.forename: Sandra
authors.initials: S
authors.lastname: Strychor
authors.forename: Erin
authors.initials: E
authors.lastname: Joseph
authors.forename: Beth A
authors.initials: BA
authors.lastname: Zamboni
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Fetterman
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Sidone
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Burke
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Curran
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006880:Hydroxy Acids / Q000097:blood; D007783:Lactones / Q000097:blood; D008081:Liposomes / Q000493:pharmacokinetics*; D051379:Mice; D016513:Mice, SCID; D017646:Organosilicon Compounds / Q000493:pharmacokinetics*; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D006880:Hydroxy Acids; D007783:Lactones; D008081:Liposomes; D017646:Organosilicon Compounds; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; D002166:Camptothecin