紫杉醇与 muramyl dipeptide 类似物缀合物新型抗肿瘤剂 MTC-220 在大鼠体内的消除。
The elimination of MTC-220, a novel anti-tumor agent of conjugate of paclitaxel and muramyl dipeptide analogue, in rats.
机构信息
Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing City 100050, China.
出版信息
Cancer Chemother Pharmacol. 2013 Jun;71(6):1453-62. doi: 10.1007/s00280-013-2144-7. Epub 2013 Apr 5.
PURPOSE
MTC-220, a conjugate of paclitaxel and muramyl dipeptide analogue, was reported to exhibit anti-tumor ability and anti-metastatic effect. The aim of present study was to investigate the elimination of MTC-220 and the related mechanisms in rats.
METHODS
The excretion of MTC-220 and its metabolites in bile and urine were determined in rats after intravenous administration at 4 mg/kg. Caco-2 cell monolayer, in situ liver perfusion model and in vivo pharmacokinetics with selected inhibitors in rats were used to confirm the involvement of hepatic transporters in the elimination of MTC-220. The metabolic stability of MTC-220 was assessed by the incubation with rat liver microsomes and plasma.
RESULTS
Approximately 72 % of MTC-220 was excreted into bile and less than 0.02 % into urine after administration in rats. The Caco-2 cell monolayer was impermeable to MTC-220. In in situ liver perfusion model, the hepatic extraction ratio of MTC-220 was reduced to 40 % of control in the presence of rifampicin, an Oatps inhibitor, and the cumulative biliary excretion rates of MTC-220 were reduced to 52.9, 71.5 and 62.9 % of control when concomitant perfusion with probenecid, novobiocin and verapamil, the inhibitors of Mrp2, Bcrp and P-gp, respectively. Co-administration of rifampicin, probenecid, novobiocin and verapamil with MTC-220 increased the AUC0-t and decreased the CL of MTC-220 in certain extents in rats. MTC-220 remained metabolically intact in rat liver microsomes, but less stable in plasma incubation.
CONCLUSIONS
In summary, the elimination of MTC-220 was mainly through the biliary excretion in unchanged form in rats. Liver transporters including Oatps, Mrp2, Bcrp and P-gp might be all involved in the hepatic elimination of MTC-220. MTC-220 exhibited the high metabolic stability in liver microsomes, but less stable in plasma. The esterases might involve in the metabolism of MTC-220 in plasma.
目的
MTC-220 是紫杉醇与 muramyl 二肽类似物的缀合物，据报道具有抗肿瘤和抗转移作用。本研究旨在探讨 MTC-220 在大鼠体内的消除及其相关机制。
方法
大鼠静脉注射 4mg/kg MTC-220 后，测定胆汁和尿液中 MTC-220 及其代谢物的排泄情况。采用 Caco-2 单层细胞、原位肝灌流模型和大鼠体内药代动力学实验，并用选定的抑制剂来证实 MTC-220 的消除是否涉及肝转运体。采用大鼠肝微粒体和血浆孵育来评估 MTC-220 的代谢稳定性。
结果
大鼠给予 MTC-220 后，约 72%的原型药物经胆汁排泄，少于 0.02%的原型药物经尿液排泄。MTC-220 在 Caco-2 单层细胞中几乎不可渗透。在原位肝灌流模型中，当用利福平（Oatps 抑制剂）处理时，MTC-220 的肝摄取率降低至对照的 40%，当与丙磺舒、新生霉素和维拉帕米（Mrp2、Bcrp 和 P-gp 的抑制剂）同时灌流时，MTC-220 的胆汁累积排泄率分别降低至对照的 52.9%、71.5%和 62.9%。在大鼠体内，利福平、丙磺舒、新生霉素和维拉帕米与 MTC-220 同时给药可在一定程度上增加 MTC-220 的 AUC0-t 和降低其 CL。MTC-220 在大鼠肝微粒体中保持代谢完整，但在血浆孵育中不太稳定。
结论
综上所述，MTC-220 在大鼠体内主要以原形经胆汁排泄消除。肝转运体包括 Oatps、Mrp2、Bcrp 和 P-gp 可能都参与了 MTC-220 的肝消除。MTC-220 在肝微粒体中表现出较高的代谢稳定性，但在血浆中不太稳定。酯酶可能参与 MTC-220 在血浆中的代谢。
Zotero 插件