Influence of Nutritional Status on the Absorption of Polyphyllin I, an Anticancer Candidate from Paris polyphylla in Rats
Influence of Nutritional Status on the Absorption of Polyphyllin I, an Anticancer Candidate from Paris polyphylla in Rats
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DOI：
10.1007/s13318-018-0473-y
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发表时间：
2018-03
影响因子：
1.9
通讯作者：
Feng-Ling Yu;Wei-Liang Gong;Fangjiang Xu;Jun-Wen Wu;S. Shakya;He Zhu
中科院分区：
文献类型：
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作者：
Feng-Ling Yu;Wei-Liang Gong;Fangjiang Xu;Jun-Wen Wu;S. Shakya;He Zhu
背景与目的蛋白质-热量营养不良（PCM）是癌症患者最常见的并发症之一。Polyphyllin I（PPI）是从重楼根茎中分离得到的一种皂苷类化合物，具有潜在的抗癌活性.在这项研究中，营养状况对PPI在大鼠口服后的吸收的影响进行了探讨。方法PCM大鼠，即营养不良（MN）大鼠，从营养良好（WN）大鼠通过热量限制协议诱导。采用药代动力学和肠灌流法评价PPI在WN和MN大鼠的肠吸收。根据体内肠道渗透性、肠道外排性和PPI消耗情况，探讨了两组之间的潜在机制。通过测定血清中细胞旁标志物转运浓度和肠连接蛋白的表达来分析肠通透性。通过比较肠内P-糖蛋白（P-gp）的蛋白水平来评价肠外排，并通过液相色谱三重四极杆质谱分析PPI在肝和肠内的消耗和/或其代谢产物的产生结果与WN大鼠相比，MN大鼠PPI的口服全身暴露量显著增加，表现为最大血药浓度（Cmax）和血药浓度-时间曲线下面积（AUC 0 - 60 h）显著增加2.51倍和3.71倍以上，终末消除半衰期（t1/2）从7.3 h延长至14.1 h。进一步的研究表明，其潜在的机制可能与改善肠道吸收和抑制PPI在MN大鼠中的去糖基化有关。此外，PPI在MN大鼠的肠吸收增强得益于肠通透性增加和肠外排减少。同时，前者表现为细胞旁标志物转运增加，连接蛋白水平降低，后者表现为P-gp表达降低。结论PPI口服暴露在MN大鼠中增强，提示营养状况改变PPI的吸收，因此在PCM癌症患者的治疗过程中，PPI的剂量应加以调整。
Background and ObjectivesProtein–calorie malnutrition (PCM) is one of the most suffered complications in cancer patients. Polyphyllin I (PPI), a saponin isolated from rhizome ofParis polyphylla, is a potential candidate in cancer therapy. In this study, the influence of nutritional status on the absorption of PPI in rats was explored after oral administration.MethodsPCM rats, namely mal-nourished (MN) rats, were induced from well-nourished (WN) rats by caloric restriction protocol. Intestinal absorption of PPI in WN and MN rats was evaluated by pharmacokinetic and intestinal perfusion methods. The potential mechanisms between two groups were investigated on the basis of intestinal permeability, intestinal efflux and PPI’s depletions in vivo. The intestinal permeability was analyzed by determining the concentration of paracellular marker transport in serum and the expression of junction proteins in intestine. The intestinal efflux was evaluated through comparing the protein level of P-glycoprotein (P-gp) in intestine, and the depletions of PPI and/or generation of its metabolites in liver and intestines were analyzed by liquid chromatography triple quadrupole mass spectrometry (LC–MS/MS) method.ResultsCompared to WN rats, the oral systemic exposure of PPI was significantly increased in MN rats, evidenced by significant enhancement of maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–60h) by more than 2.51- and 3.71-folds as well as terminal elimination half-life (t1/2) prolonged from to 7.3 to 14.1 h. Further studies revealed that the potential mechanism might be associated with combined contribution of improved intestinal absorption and depressed deglycosylation of PPI in MN rats. Furthermore, enhanced intestinal absorption of PPI was benefited from increased intestinal permeability and decreased intestinal efflux in MN rats. Meanwhile, the former manifested as increased transport of paracellular marker and decreased junction proteins levels, while the later evidenced by reduced P-gp expression.ConclusionsThe oral exposure of PPI was enhanced in MN rats, which suggested that nutritional status alters the absorption of PPI, and thus the dosage of PPI should be modified during the treatment of cancer patient with PCM.