Co-administration of piperine and docetaxel results in improved anti-tumor efficacy via inhibition of CYP3A4 activity.
Co-administration of piperine and docetaxel results in improved anti-tumor efficacy via inhibition of CYP3A4 activity.
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通过抑制CYP3A4活性，对载磷脂和多西他赛的共同给药可提高抗肿瘤功效。
DOI：
10.1002/pros.21469
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发表时间：
2012-05-01
期刊：
影响因子：
2.8
通讯作者：
Kolenko, Vladimir M.
中科院分区：
文献类型：
--
作者：
Makhov, Peter;Golovine, Konstantin;Canter, Daniel;Kutikov, Alexander;Simhan, Jay;Corlew, Melany M.;Uzzo, Robert G.;Kolenko, Vladimir M.
多西他赛是FDA批准的用于去势抵抗性前列腺癌（CRPC）的主流治疗药物，但其给药仅能将中位生存期提高2至4个月。多西紫杉醇通过肝脏CYP3A4活性在肝脏代谢。胡椒碱是一种主要的植物生物碱/酰胺，已被证明在无细胞系统中抑制CYP3A4酶的活性。因此，我们研究胡椒碱与多西紫杉醇合用是否能提高多西紫杉醇的体内体外药动学活性。荧光法测定肝脏CYP3A4酶活性。采用液相色谱法分析多西他赛体内药动学活性。采用人CRPC体内异种移植模型，评价多西他赛与胡椒碱联合给药的抗肿瘤效果。与多西紫杉醇单独给药相比，抑制肝脏CYP3A4活性导致多西紫杉醇曲线下面积（AUC）、半衰期和最大血浆浓度增加。胡椒碱和多西紫杉醇协同施用可显著提高多西紫杉醇在人CRPC异种移植模型中的抗肿瘤效果。多西紫杉醇是应用最广泛的细胞毒性化疗药物之一，目前是转移性CRPC的主要治疗药物。膳食成分是影响药物代谢和转运的重要因素。在我们的研究中，饮食中摄入胡椒碱增加了多西紫杉醇在异种移植模型中的治疗效果，而不会对治疗小鼠产生更多的不良反应。
Docetaxel is the mainline treatment approved by the FDA for castration-resistant prostate cancer (CRPC) yet its administration only increases median survival by two to four months. Docetaxel is metabolized in the liver by hepatic CYP3A4 activity. Piperine, a major plant alkaloid/amide, has been shown to inhibit the CYP3A4 enzymatic activity in a cell-free system. Thus, we investigated whether the co-administration of piperine and docetaxel could increase docetaxel’s pharmacokinetic activity in vitro and in vivo. Liver CYP3A4 enzymatic activity was measured by fluorescence. In vivo docetaxel pharmacokinetic activity was analyzed by liquid chromatography. An in vivo xenograft model of human CRPC was utilized to assess the anti-tumor effect of docetaxel when co-administered with piperine. Inhibition of hepatic CYP3A4 activity resulted in an increased area under the curve (AUC), half-life and maximum plasma concentration of docetaxel when compared to docetaxel alone administration. The synergistic administration of piperine and docetaxel significantly improved the anti-tumor efficacy of docetaxel in a xenograft model of human CRPC. Docetaxel is one of the most widely used cytotoxic chemotherapeutic agents and is currently the mainstay treatment for metastatic CRPC. Dietary constituents are important agents modifying drug metabolism and transport. In our studies, dietary consumption of piperine increases the therapeutic efficacy of docetaxel in a xenograft model without inducing more adverse effects on the treated mice.
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影响因子：
45.3
作者：
Bruno, R;Hille, D;Sheiner, LB
通讯作者：
Sheiner, LB
影响因子：
6.2
作者：
Van Veldhuizen, PJ;Reed, G;Williamson, S
通讯作者：
Williamson, S
影响因子：
3.8
作者：
Kakarala, Madhuri;Brenner, Dean E.;Korkaya, Hasan;Cheng, Connie;Tazi, Karim;Ginestier, Christophe;Liu, Suling;Dontu, Gabriela;Wicha, Max S.
通讯作者：
Wicha, Max S.
影响因子：
11.5
作者：
To, H;Shin, M;Ohdo, S
通讯作者：
Ohdo, S
影响因子：
8.8
作者：
Engels, FK;Sparreboom, A;Mathot, RAA;Verweij, J
通讯作者：
Verweij, J