通过共同施用P-糖蛋白抑制剂KR30031可以提高紫杉醇的口服生物利用度。,Pharmaceutical Research

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通过共同施用P-糖蛋白抑制剂KR30031可以提高紫杉醇的口服生物利用度。
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2003 Jan
Woo, Jong Soo, Lee, Chang Hyun, Shim, Chang Koo, Hwang, Sung-Joo

目的：为改善紫杉醇的口服生物利用度，将一种新型的P-糖蛋白抑制剂KR30031与紫杉醇共同给药，该抑制剂是维拉帕米类似物，具有较少的心血管作用，并阐明了造成紫杉醇口服生物利用度低的其他可能原因，肝代谢抑制剂酮康唑也可以与紫杉醇并用。方法：在大鼠中测试了体内口服吸收，还对Caco-2细胞单层进行了体外研究，以鉴定P-糖蛋白抑制的程度。结果：紫杉醇与酮康唑，KR-30031或KR-30031和酮康唑并用后，生物利用度分别比对照组提高了约1.6倍，7.5倍或8.9倍。这些结果表明，P-糖蛋白在紫杉醇的口服生物利用度中起主要作用。相对于KR-30031的P-糖蛋白抑制作用，酮康唑对紫杉醇口服生物利用度的作用受到限制。Caco-2细胞转运的体外研究表明，与从根尖侧渗透相比，从基底外侧给药时紫杉醇的渗透显着更高，表明酶反应参与了主动外排机制。在KR-30031的存在下紫杉醇根尖到基底外侧的转运增加。KR-30031减少这种外排转运的能力与维拉帕米（一种众所周知的P-糖蛋白抑制剂）的能力相同。结论：我们的研究结果表明，约54％的紫杉醇口服剂量是通过P-糖蛋白挤出到肠腔中的。

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Enhanced oral bioavailability of paclitaxel by coadministration of the P-glycoprotein inhibitor KR30031.

PURPOSE: In an attempt to improve the oral bioavailability of paclitaxel, a novel P-glycoprotein inhibitor, KR30031, which is verapamil analog with fewer cardiovascular effects, was coadministered with paclitaxel, and to elucidate other possible causes of the low oral bioavailability of paclitaxel, an inhibitor of hepatic metabolism, ketoconazole, was also coadministered with paclitaxel. METHODS: In vivo oral absorption was tested in rats, and an in vitro study was also performed with a Caco-2 cell monolayer to identify the extent of P-glycoprotein inhibition. RESULTS: After coadministration of paclitaxel with ketoconazole, KR-30031, or KR-30031 and ketoconazole, bioavailability was increased about 1.6-, 7.5-, or 8.9-fold as compared with control, respectively. These results show that P-glycoprotein plays a major role in the oral bioavailability of paclitaxel. The effect of ketoconazole on oral bioavailability of paclitaxel was limited relative to the P-glycoprotein inhibition effect of KR-30031. In vitro study of Caco-2 cell transport showed that paclitaxel permeation was significantly higher when the drug was given from the basolateral side as compared to the permeation from the apical side, indicating the involvement of an enzyme reaction in the active efflux mechanism. Apical-to-basolateral transport of paclitaxel was increased in the presence of KR-30031. The ability of KR-30031 to reduce this efflux transport is equal to that of verapamil, a well-known P-glycoprotein inhibitor. CONCLUSIONS: Our findings suggest that about 54% of a paclitaxel oral dose is extruded to the gut lumen by P-glycoprotein. Thus, the bioavailability of paclitaxel could be enhanced by coadministration of a P-glycoprotein inhibitor, KR-30031.

更新日期：2017-01-31

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