Faculty of Pharmacy, University of Montreal, P.O. Box 6128, Downtown Station, Montreal, QC, Canada H3C 3J7.
ACS Nano. 2010 Dec 28;4(12):7552-8. doi: 10.1021/nn101924a. Epub 2010 Nov 10.
Injectable scavenging nanocarriers have been proposed as detoxifying agents when there are no specific antidotes to treat pharmacological overdoses. They act by capturing the drug in situ, thereby restricting distribution in tissues. In the clinic, the only systems used for that purpose are parenteral lipid emulsions, which are relatively inefficient in terms of uptake capacity. In this study, we investigated long-circulating liposomes with a transmembrane pH gradient as treatment for diltiazem intoxication. The unique ion-trapping properties of the vesicles toward ionizable compounds were exploited to sequester the drug in the bloodstream and limit its pharmacological effect. After in vitro optimization of the formulation, the in vivo scavenging properties of the liposomes were demonstrated by examining the drug's pharmacokinetics. The reduced volume of distribution and increased area under the plasma concentration versus time curve in animals treated with liposomes indicated limited tissue distribution. The vesicles exerted a similar but more pronounced effect on deacetyl-diltiazem, the principal active metabolite of the drug. This in vivo uptake of both drug and metabolite altered the overall pharmacological outcome. In rats receiving an intravenous bolus of diltiazem, the liposomes tempered the hypotensive decline and maintained higher average blood pressure for 1 h. The detoxifying action of liposomes was even stronger when the rats received higher doses of the drug via perfusion. In conclusion, the present work provided clear evidence that liposomes with a transmembrane pH gradient are able to change the pharmacokinetics and pharmacodynamics of diltiazem and its metabolite and confirmed their potential as efficient detoxifying nanocarriers.
当没有特定的解毒剂来治疗药物过量时，可注射的清除纳米载体被提议作为解毒剂。它们通过就地捕获药物来发挥作用，从而限制药物在组织中的分布。在临床上，唯一用于该目的的系统是肠外脂质乳剂，但其摄取能力相对较低。在这项研究中，我们研究了具有跨膜 pH 梯度的长循环脂质体作为地尔硫卓中毒的治疗方法。利用囊泡对可电离化合物的独特离子捕获特性，将药物隔离在血液中，限制其药理作用。在对配方进行体外优化后，通过检查药物的药代动力学来证明脂质体的体内清除特性。与用脂质体处理的动物相比，药物的分布体积减小，血浆浓度-时间曲线下面积增加，表明组织分布受限。这些囊泡对地尔硫卓的主要活性代谢物去乙酰地尔硫卓产生了类似但更明显的作用。药物和代谢物的这种体内摄取改变了整体药理结果。在接受地尔硫卓静脉推注的大鼠中，脂质体缓解了低血压下降，并在 1 小时内维持了更高的平均血压。当大鼠通过灌注接受更高剂量的药物时，脂质体的解毒作用甚至更强。总之，本研究提供了明确的证据，表明具有跨膜 pH 梯度的脂质体能够改变地尔硫卓及其代谢物的药代动力学和药效学，并证实了它们作为有效解毒纳米载体的潜力。
