LDLR adenovirus

It has been assumed that only free drugs can enter tissues via active or passive transport. However, given that lipoproteins function as carriers of serum lipids such as cholesterol and triglycerides, researchers hypothesized that lipoproteins could bind to certain drugs and mediate their transport into tissues in a lipid-associated form. Here, they performed in vitro and in vivo studies using low-density lipoprotein receptor (LDLR)-overexpressing or knockdown cells and wild-type or LDLR mutant mice to show the binding of various drugs to lipoproteins and the uptake of lipoprotein-associated drugs via a lipoprotein receptor-mediated process. In clinical studies, studies on the effects of lipoprotein apheresis on serum drug concentrations in patients with familial hypercholesterolemia demonstrated that lipoprotein-mediated drug transport occurs not only in mice but also in humans. These findings represent new concepts regarding drug transport and metabolism in vivo and suggest that the role of lipoprotein-mediated drug transport should be considered in the development of effective and safe drug therapies.

To elucidate the role of LDLR in mediating VLDL/LDL-associated drug transport, the researchers used LDLR adenovirus (Ad-LDLR)-infected Hepa1-6 cells for drug uptake experiments (Figure 1A). LDLR-overexpressing cells uptake [3H] cholesterol and fluorescently labeled LDL in LDL higher than Mock-treated cells (Figure 1B), indicating that this experimental system can be used to evaluate LDLR-mediated LDL particle uptake. Subsequently, the results of the drug uptake experiment showed that LDLR overexpression significantly increased the uptake of LDL-associated P2Y12 receptor antagonists (Figure 1C-E).

Figure 1. Effect of LDLR overexpression on LDL-mediated drug transport in vitro. (Yamamoto H, et al., 2017)