Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, 565-8565, Japan.
Sci Rep. 2017 Apr 4;7(1):633. doi: 10.1038/s41598-017-00685-9.
Only free drugs have been believed to be carried into tissues through active or passive transport. However, considering that lipoproteins function as carriers of serum lipids such as cholesterol and triglycerides, we hypothesized that lipoproteins can associate with certain drugs and mediate their transport into tissues in lipid-associated form. Here, in vitro and in vivo studies with low density lipoprotein receptor (LDLR)-overexpressing or -knockdown cells and wild-type or LDLR-mutant mice were used to show the association of various drugs with lipoproteins and the uptake of lipoprotein-associated drugs through a lipoprotein receptor-mediated process. In clinical studies, investigation of the effect of lipoprotein apheresis on serum drug concentrations in patients with familial hypercholesterolemia demonstrated that lipoprotein-mediated drug transport occurs in humans as well as in mice. These findings represent a new concept regarding the transport and metabolism of drugs in the body and suggest that the role of lipoprotein-mediated drug transport should be considered when developing effective and safe pharmacotherapies.
人们一直认为，只有游离型药物能够通过主动或被动转运的方式进入组织。然而，鉴于载脂蛋白作为胆固醇和甘油三酯等血清脂质的载体发挥作用，我们假设载脂蛋白可以与某些药物结合，并以脂联形式将其转运至组织中。在这里，通过低密度脂蛋白受体（LDLR）过表达或敲低细胞以及野生型或 LDLR 突变小鼠的体外和体内研究，我们证明了各种药物与载脂蛋白的结合以及通过载脂蛋白受体介导的过程摄取脂联型药物。在临床研究中，脂蛋白吸附术对家族性高胆固醇血症患者血清药物浓度的影响的研究表明，载脂蛋白介导的药物转运不仅存在于小鼠，也存在于人类体内。这些发现代表了一种关于药物在体内转运和代谢的新概念，并提示在开发有效和安全的药物治疗方法时，应考虑载脂蛋白介导的药物转运的作用。
