香加皮强心成分杠柳毒苷肠菌代谢研究

[目的]检测杠柳毒苷在大鼠和人体肠菌作用下含量与成分的变化。[方法]采用离体粪便温孵法,利用高效液相—紫外法对温孵不同时间的杠柳毒苷及其代谢产物含量进行测定,并利用高效液相—质谱联用法对代谢物进行鉴定。[结果]杠柳毒苷含量随温孵时间的延长呈快速下降的趋势,温孵5h含量降低约75%,与此同时有代谢物生成,并随温孵时间的延长呈上升趋势。[结论]杠柳毒苷在肠菌(大鼠/人体)作用下,代谢迅速,生成了代谢产物杠柳次苷。     

Periplocymarin is a potential natural compound for drug development: highly permeable with absence of P‐glycoprotein efflux and cytochrome P450 inhibitions

Periplocymarin, a cardiac glycoside isolated from Periploca sepium (P. sepium) and Periploca graeca (P. graeca), is a potential anti‐cancer compound. The aim of the study was to investigate the potential for periplocymarin to interact with P‐glycoprotein (P‐gp) and to inhibit cytochrome P450s known to be expressed in the human small intestine. The in vitro and in situ permeability of periplocymarin were studied using Madin‐Darby canine kidney (MDCK‐II‐WT) cells transfected with or without the human multidrug resistance (MDR1) gene and the single‐pass perfused rat intestinal model. The cell system exhibited high functional activity and a net efflux ratio (NER) of 4.32 after transport of Rhodamine 123 (R123) (the P‐gp substrate). Periplocymarin is highly permeable (P_app > 10 × 10^‐6 cm/s; P_eff(rat) > 5.09 × 10^‐5 cm/s) and independent of P‐gp influences. The NER at 100 μm periplocymarin (0.8) was unchanged in the presence of cyclosporine A (a non‐specific P‐gp inhibitor) (0.82). In the single‐pass intestinal model, the P_{eff (rat)} of 5 µg/ml periplocymarin (5.490 × 10^‐5 cm/s) did not change in the presence of cyclosporine A (5.394 × 10^‐5 cm/s). In the R123‐inhibition assay, periplocymarin did not competitively inhibit P‐gp. The inhibitory potential of periplocymarin on cytochrome P450 (CYP450s) was also studied. Periplocymarin (5, 50 μm ) did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Thus, periplocymarin is unlikely to encounter drug–drug interactions with P‐gp and CYP450s. Periplocymarin could be taken forward for further studies in drug development to test bioavailability, Phase II enzyme interactions and additional transporter interactions. Copyright © 2014 John Wiley & Sons, Ltd.     

三七总皂苷对杠柳毒苷代谢产物杠柳次苷药代动力学的影响

[目的]研究三七总皂苷对杠柳毒苷代谢产物杠柳次苷药代动力学的影响。[方法]将18只SD大鼠随机分为杠柳毒苷单独给药组、杠柳毒苷与低剂量三七总皂苷配伍组、杠柳毒苷与高剂量三七总皂苷配伍组3组,每组6只。各组大鼠连续灌胃给药7 d后,采集不同时间点的血浆样品,测定血浆中杠柳次苷的含量,并计算其药代动力学参数。[结果]三七总皂苷配伍杠柳毒苷后,杠柳毒苷代谢产物杠柳次苷在大鼠血浆中的主要药动学参数C_max、T_max、AUC_0-t、AUC_0-∞与杠柳毒苷单独给药相比具有统计学差异。[结论]三七总皂苷与杠柳毒苷配伍使用可使杠柳毒苷代谢产物杠柳次苷的药代动力学行为发生改变。     

杠柳毒苷、杠柳次苷及杠柳苷元生物药剂学分类研究

目的采用生物药剂学分类系统(Biopharmaceuticals Classification System,BCS)对杠柳毒苷、杠柳次苷及杠柳苷元进行生物药剂学分类研究。方法采用实验和计算机预测软件Pipeline Pilot 8.5、ChemDraw研究杠柳毒苷、杠柳次苷和杠柳苷元的溶解性和渗透性,根据实验值和预测值利用BCS分类方法对3者进行分类。结果根据实验结果杠柳毒苷、杠柳次苷和杠柳苷元均为BCSⅢ类药物,与不同软件预测的分类结果存在差异。基于Clg P的渗透性结果与实验结果一致;基于lg Cs的溶解性及基于Alg P、lg D的渗透性预测结果与实验结果相反。结论杠柳毒苷、杠柳次苷和杠柳苷元均为BCS Ⅲ类药物,3者溶解性依次降低,但仍都属于高溶解性成分。3者的渗透性是影响其吸收的关键因素。基于化学结构对甲型强心苷类药物活性成分进行的生物药剂学属性预测值与实验结果存在较大差异,对含此类成分的中药制剂的口服吸收进行BCS研究及体内外相关性评价时建议采用多种方法对数据进行校正,增加结果的可靠性。     

Redox-responsive PEGylated self-assembled prodrug-nanoparticles formed by single disulfide bond bridge periplocymarin-vitamin E conjugate for liver cancer chemotherapy

Periplocymarin (PPM), a cardiac glycoside, has a narrow therapeutic index, poor tumor selectivity and severe cardiovascular toxicity which hinder its wide clinical applications in cancer treatment. Herein, we report novel redox-responsive prodrug-nanoparticles (MPSSV-NPs) self-assembled by co-nanoprecipitation of PPM-vitamin E conjugate and a PEG derivative of linoleate (mPEG2000-LA) in water. It was found that the characteristics of PPM-vitamin E nanoparticles (PSSV-NPs) were improved through co-nanoprecipitation with increased percentages of mPEG2000-LA. Moreover, the MPSSV-NPs were optimized according to the in vitro release and cytotoxicity study. Furthermore, the optimized MPSSV-NPs dramatically enhanced the circulation time and tumor distribution of PSSV-NPs after single intravenous injection. The in vivo studies in malignant H₂₂-bearing mice revealed that MPSSV-NPs could effectively suppress tumor growth without causing obvious systemic toxicity. Altogether, these results suggested that MPSSV-NPs could offer a safe, multifunctional and viable nanoplatform for cardiac glycosides in cancer treatment.