Clindamycin-paclitaxel pharmacokinetic interaction in ovarian cancer patients
Clindamycin-paclitaxel pharmacokinetic interaction in ovarian cancer patients
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DOI：
10.1007/s00280-005-0160-y
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发表时间：
2006-09-01
影响因子：
3
通讯作者：
Zucchetti, Massimo
中科院分区：
文献类型：
--
作者：
Fruscio, Robert;Lissoni, Andrea A.;Zucchetti, Massimo
引言：血浆蛋白结合率是许多药物的重要因素，可影响药物的组织分布和药代动力学。α（1）-酸性糖蛋白（AGP）是一种急性期蛋白，其可在患有包括癌症在内的多种病理状况的患者的血浆中增加。在培养的细胞中进行的研究表明，紫杉醇的细胞毒性通过添加AGP而降低，并且通过用克林霉素取代其与AGP的结合而恢复对紫杉醇的敏感性，导致紫杉醇细胞摄取增加。本研究的目的是评估克林霉素是否也改变了紫杉醇在癌症患者中的药代动力学。患者和方法：本研究纳入了16例晚期卵巢癌患者，既往接受过手术和化疗。在每例患者巩固治疗（紫杉醇和卡铂）的前三个周期进行紫杉醇的药代动力学研究。在这些周期中，紫杉醇单独给药，并与两种不同剂量（600和1,200 mg）的克林霉素同时给药。随机分配每例患者的三种治疗顺序，以避免相同的治疗顺序。结果：克林霉素可部分改变紫杉醇的药代动力学。紫杉醇单独给药时的C-max和AUC（0-last）显著高于与1，200 mg克林霉素联合给药时。此外，AGP浓度似乎对紫杉醇药代动力学具有较小但统计学显着的影响，因为当紫杉醇单独给药时，AUC（0-last）与AGP血浆浓度呈显着正相关。当紫杉醇与1,200 mg克林霉素联合给药时，线性关系丧失。克林霉素的联合给药对毒性没有影响。结论：克林霉素影响紫杉醇药代动力学的假设得到了证实。然而，两种药物联合给药引起的变化极小，因此临床相关性值得怀疑。
Introduction: Plasma protein binding is an important factor for many drugs that can influence the tissue distribution and pharmacokinetics. alpha(1)-acid glycoprotein (AGP) is an acute-phase protein that can increase in plasma of patients with several pathological conditions including cancer. Studies performed in cultured cells indicate that paclitaxel cytotoxicity is reduced by adding AGP and the sensitivity to paclitaxel is restored by displacing its binding to AGP with clindamycin, resulting in an increased paclitaxel cell uptake. The purpose of this study was to evaluate whether clindamycin modifies paclitaxel pharmacokinetics also in cancer patients. Patients and methods: Sixteen patients with advanced ovarian cancer, previously treated with surgery and chemotherapy were enrolled in this study. A pharmacokinetic study of paclitaxel was performed in the first three cycles of the consolidation therapy (paclitaxel and carboplatin) in each patient. In these cycles paclitaxel was administered alone and with two different doses (600 and 1,200 mg) of concurrent clindamycin. The sequence of the three treatments was randomly assigned in each patient in order to avoid the same order of treatments. Results: Paclitaxel pharmacokinetics were partly modified by the concurrent administration of clindamycin. C-max and AUC(0-last) of paclitaxel were significantly higher when the drug was given alone than when it was coadministered with 1,200 mg clindamycin. Moreover, AGP concentrations seem to have a small but statistically significant influence on paclitaxel pharmacokinetic, since AUC(0-last) showed a positive significant correlation with AGP plasma concentration when paclitaxel was given alone. The linear relation was lost when paclitaxel was coadministered with 1,200 mg clindamycin. Toxicity was not influenced by the coadministration of clindamycin. Conclusion: The hypothesis that clindamycin could affect paclitaxel pharmacokinetics seems to be verified with this study. Nevertheless, changes induced by giving the combination of the two drugs are minimal and thus of questionable clinical relevance.