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不同肠道微环境下奈妥匹坦帕洛诺司琼胶囊对大鼠白蛋白紫杉醇药动学的影响
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| 篇名： | 不同肠道微环境下奈妥匹坦帕洛诺司琼胶囊对大鼠白蛋白紫杉醇药动学的影响 |
| TITLE： | Effects of Netupitant and palonosetron hydrochloride capsules on the pharmacokinetics of albumin-bound paclitaxel in rats under different intestinal microenvironments |
| 摘要： | 目的 探究不同肠道微环境下奈妥匹坦帕洛诺司琼胶囊（NEPA）对大鼠注射用紫杉醇（白蛋白结合型）（简称“白蛋白紫杉醇”）药动学的影响。方法将雄性SD大鼠分为正常组和模型组，每组16只。模型组大鼠灌胃万古霉素溶液构建肠道紊乱大鼠模型。造模后次日，分析其肠道菌群多样性，并检测其小肠及肝组织中细胞色素P4503A1（CYP3A1）、CYP2C11mRNA及肝组织中上述蛋白的表达。将雄性SD大鼠按前述方法分组，每组16只；将正常组分为TP化疗组（TP-1组）、TP化疗+NEPA组（TP+NEPA-1组），将模型组大鼠随机分为TP化疗组（TP-2组）、TP化疗+NEPA组（TP+NEPA-2组），每组8只。TP+NEPA-1组和TP+NEPA-2组大鼠分别单次灌胃NEPA混悬液25.8mg/kg（以奈妥匹坦计）；1h后，4组大鼠均单次尾静脉注射白蛋白紫杉醇和顺铂药液。于末次给药后的不同时间点采集血样，以阿奇霉素为内标，采用液相色谱-串联质谱法检测血浆中紫杉醇的质量浓度，并采用DAS2.0计算其主要药动学参数并进行组间比较。结果与正常组大鼠相比，模型组大鼠的Chao1、Shannon指数均显著降低（P＜0.05），菌群组成及相对丰度变化明显；其肝组织中CYP3A1mRNA、小肠及肝组织中CYP2C11mRNA的表达均显著下调（P＜0.05）。与TP-1组比较，TP-2组大鼠体内紫杉醇的药时曲线下面积（AUC0－t、AUC0－∞）、平均滞留时间（MRT0－），tTP+NEPA-1组及TP+NEPA-2组大鼠体内紫杉醇的达峰浓度（cmax）、AUC0－t、AUC0－∞均显著升高或延长；TP-2组大鼠体内紫杉醇的清除率（CL），TP+NEPA-1组及TP+NEPA-2组大鼠体内紫杉醇的表观分布容积（Vd）、CL均显著降低或缩短（P＜0.05）。与TP-2组比较，TP+NEPA-2组大鼠体内紫杉醇的cmax显著升高，Vd、MRT0－t均显著降低或缩短（P＜0.05）。结论肠道菌群紊乱会影响CYP3A1、CYP2C11mRNA的表达，导致紫杉醇在大鼠体内的清除减慢，暴露量增加；肠道菌群正常时，联用NEPA可增加紫杉醇在大鼠体内的暴露量；肠道菌群紊乱时，联用NEPA对紫杉醇体内暴露量的影响有限。 |
| ABSTRACT： | OBJECTIVE To investigate the impact of Netupitant and palonosetron hydrochloride capsules （NEPA） on the pharmacokinetics of Paclitaxel for injection （albumin bound） （i. e. albumin-bound paclitaxel） under different intestinal microenvironment conditions. METHODS Male SD rats were divided into a normal group and a model group （n＝16）. Rats in the model group were intragastrically administered vancomycin solution to establish an intestinal disorder model. The next day after modeling， intestinal microbiota diversity was analyzed， and the mRNA expressions of cytochrome P450 3A1 （CYP3A1） and CYP2C11 in small intestine and liver tissues as well as those protein expressions in liver tissue were measured. Male SD rats were grouped as described above （n＝16）. The normal group was subdivided into the TP chemotherapy group （TP-1 group） and the TP chemotherapy+NEPA group （TP+NEPA-1 group）； the model group was subdivided into the TP chemotherapy group （TP-2 group） and the TP chemotherapy+NEPA group （TP+NEPA-2 group） （n＝8）. Rats in the TP+NEPA-1 and TP+NEPA-2 groups received a single intragastric dose of NEPA suspension （25.8 mg/kg， calculated by netupitant）. One hour later， all four groups received a single tail vein injection of albumin-bound paclitaxel and cisplatin. Blood samples were collected at different time points after the last administration. Using azithromycin as the internal standard， plasma paclitaxel concentrations were determined by liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters were calculated using DAS 2.0 software and compared between groups. RESULTS Compared with the normal group， the model group showed significantly decreased Chao1 and Shannon indexes （P＜0.05）， significant alterations in microbiota composition and relative abundance， and significantly downregulated expressions of CYP3A1 mRNA in liver tissue and CYP2C11 mRNA in both small intestine and liver tissues （P＜0.05）. Compared with the TP-1 group， the AUC0－t， AUC0－∞， MRT0－t of paclitaxel in the TP-2 group， the cmax， AUC0－t， AUC0－∞ of paclitaxel in the TP+NEPA-1 group and TP+NEPA-2 group were significantly increased or prolonged； CL of paclitaxel in the TP-2 group， Vd and CL of paclitaxel in the TP+NEPA-1 group and the TP+NEPA-2 group were significantly decreased or shortened （P＜0.05）. Compared with the TP-2 group， cmax of paclitaxel in the TP+NEPA-2 group was significantly increased， and Vd and MRT0－t were significantly decreased or shortened （P＜0.05）. CONCLUSIONS Intestinal microbiota disorder affects the mRNA expressions of CYP3A1 and CYP2C11， leading to decreased clearance and increased systemic exposure of paclitaxel. Concomitant administration of NEPA under normal intestinal microbiota condition increases paclitaxel exposure. However， under conditions of intestinal microbiota disorder， concomitant administration of NEPA has a limited impact on paclitaxel systemic exposure. |
| 期刊： | 2025年第36卷第16期 |
| 作者： | 秦源蔓；褚文昊；许佳祺；李雨桐；梁博；张学良；刘剑 |
| AUTHORS： | QIN Yuanman，CHU Wenhao，XU Jiaqi，LI Yutong，LIANG Bo，ZHANG Xueliang，LIU Jian |
| 关键字： | 奈妥匹坦帕洛诺司琼；白蛋白紫杉醇；肠道菌群；药动学；药物相互作用 |
| KEYWORDS： | netupitant and palonosetron； albumin-bound paclitaxel； gut microbiota； pharmacokinetics； drug interactions |
| 阅读数： | 5 次 |
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