Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.
Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.
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C.B-17 SCID 小鼠中非脂质体 DB-67 和脂质体 DB-67 的血浆和组织分布。
DOI：
10.1007/s10637-007-9109-9
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发表时间：
2008
影响因子：
3.4
通讯作者：
Eiseman,JulieL
中科院分区：
文献类型：
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作者：
Zamboni,WilliamC;Jung,LauraL;Strychor,Sandra;Joseph,Erin;Zamboni,BethA;Fetterman,SarahA;Sidone,BrianJ;Burke,ThomasG;Curran,DennisP;Eiseman,JulieL
目的：DB-67是一种硅胶，7-硅基修饰的喜树碱，具有增强的亲脂性和活性内酯环的血液稳定性。DB-67脂质体制剂的产生可能是一种有吸引力的静脉(IV)给药方法，并且可以保持DB-67的活性-内酯形式。方法：采用联合免疫缺陷小鼠模型，尾静脉注射非脂质体(NL)和脂质体(L)DB-67 10 mg/kg， × 1，观察DB-67内酯和羟基酸的组织和血浆分布。给药后，处死小鼠(n= ，每个时间点3只)，于给药后5min~48h采集血液(∼1ml)和组织标本。结果：口服NL-DB-67和L-DB-67后，DB-67内酯的清除量分别为1.6g/h/h和3.5g/h/m2，口服NL-DB-67和L-DB-67后的半衰期分别为1.4h和0.9h。注射NL-DB-67和L-DB-67后，血浆中DB-67内酯的百分含量分别为92%和89%。与NL-DB-67相比，L-DB-67对肝、肾、脾、肺组织的暴露时间较长。结论：在血浆中，NL-DB-67和L-DB-67作用后，DB-67大部分仍以内酯形式存在。服用NL-DB-67和L-DB-67后，DB-67的血药浓度相似，表明DB-67的大部分立即从L-DB-67制剂中释放。注射L-DB-67后，与NL-DB-67相比，DB-67在脾组织中的暴露时间更长且更高，这与网状内皮系统对脂质体的清除一致。
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.