Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice
Efficacy of novel P-glycoprotein inhibitors to increase the oral uptake of paclitaxel in mice
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DOI：
10.1023/b:drug.0000026248.45084.21
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发表时间：
2004-08-01
影响因子：
3.4
通讯作者：
van Tellingen, O
中科院分区：
文献类型：
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作者：
Bardelmeijer, HA;Ouwehand, M;van Tellingen, O
P-糖蛋白抑制剂可提高紫杉醇的口服生物利用度。我们现在已经在体内和体外实验中探索了几种新型P-糖蛋白抑制剂增加紫杉醇从小鼠肠道吸收的有效性的机制。所研究的抑制剂为环孢素A、PSC 833、GF120918、LY335979和R101933。质量平衡研究表明，GF120918是最有效的抑制剂，导致紫杉醇几乎完全被吸收。PSC 833的疗效稍差，而环孢菌素A和LY335979的疗效中等。R101933只有轻微的影响。这些发现与LLC-mdrla细胞的体外转运实验是一致的。通过对环孢素A、PSC 833和GF120918的肠道动力学研究发现，环孢素A、PSC 833和GF120918与紫杉醇同时通过胃和肠道，而LY335979和R101933延缓胃排空。此外，这些后一种化合物在释放到肠道时似乎更容易被吸收，从而降低了局部肠道浓度。由于环孢素A和PSC 833对紫杉醇的吸收和代谢消除有共同作用，导致紫杉醇在血浆中的浓度最高。总之，我们的模型提供了决定P-糖蛋白抑制剂是否适合于口服紫杉醇治疗的因素，并将有助于选择候选抑制剂进行临床测试。
P-glycoprotein inhibitors can increase the oral bioavailability of paclitaxel. We have now explored the mechanisms that determine the efficacy of several novel P-glycoprotein inhibitors to increase the absorption of paclitaxel from the gut lumen of mice in both in vivo and in vitro experiments. The inhibitors studied were cyclosporin A, PSC 833, GF120918, LY335979 and R101933. Mass balance studies showed that GF120918 was the most effective inhibitor, resulting in almost complete uptake of paclitaxel. PSC 833 was slightly less effective, whereas cyclosporin A and LY335979 were moderately effective. R101933 had only marginal effects. These findings were in line with in vitro transport experiments using LLC-mdrla cells. By studying the intra-intestinal kinetics of the agents we found that cyclosporin A, PSC 833 and GF120918 rapidly passed the stomach and traveled concurrently with paclitaxel through the intestines, whereas LY335979 and R101933 delayed stomach emptying. Moreover, these latter compounds appear to be more readily absorbed when released into the intestines thus reducing local intestinal concentrations. Due to their combined effects on absorption and metabolic elimination of paclitaxel, cyclosporin A and PSC 833 resulted in the highest paclitaxel levels in plasma. In conclusion, our models provide insight into the factors that determine the suitability of P-glycoprotein inhibitors to enable oral paclitaxel therapy and will be useful in selecting candidate inhibitors for clinical testing.