Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel
Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel
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DOI：
10.1200/jco.2001.19.4.1160
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发表时间：
2001-02-15
影响因子：
45.3
通讯作者：
Schellens, JHM
中科院分区：
文献类型：
--
作者：
Malingré, MM;Richel, DJ;Schellens, JHM
目的：多西紫杉醇的口服生物利用度很低，这至少部分是由于其对肠道药物外排泵p -糖蛋白（P-gp）的亲和力。此外，肠道和肝脏细胞色素P450 (CYP) 3A4对多西紫杉醇的代谢也可能起作用。本研究的目的是增加口服多西紫杉醇与环孢素（CsA）的全身暴露，环孢素是一种有效的P-gp抑制剂和CYP 3A4底物，患者和方法：在14例实体肿瘤患者中进行了概念验证研究。患者接受一个疗程的口服多西他赛75mg /m(2)，同时或不单独口服CsA 15mg /kg。CsA比口服多西紫杉醇早30分钟。在随后的疗程中，患者接受静脉注射（IV）多西他赛100 mg/m(2)。结果：口服多西他赛75 mg/m(2)不加CsA组患者的浓度-时间曲线下平均（+/- SD）面积为0.37 +/- 0.33 mg.h/L和2.71 +/- 1.81 mg.h/L，静脉多西他赛100 mg/m2组患者的平均AUC为4.41 +/- 2.10 mg.h/L。口服多西他赛的绝对生物利用度在没有CsA的情况下为8% +/- 6%，在有CsA的情况下为90% +/- 44%。多西紫杉醇联合CsA口服耐受良好。结论：口服CsA联合给药可显著提高多西紫杉醇的口服生物利用度。口服药物给药后全身暴露的患者间变异性与静脉给药后相同。这些数据是有希望的，并为进一步开发临床有用的口服多西紫杉醇制剂奠定了基础。
Purpose: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4, patients and Methods: A proof-of-concept study was carded out in 14 patients with solid tumors.Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2).Results: The mean (+/- SD) area under the concentral ion-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA, The mean AUC of IV docetaxel 100 mg/m2 wets 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated.Conclusion: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.