Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice
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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.
KeywordsDB-67 Silatecans Liposomes Pharmacokinetics Camptothecins
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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