Nanoparticles of Lactic Acid Polymer with Rifampicin Decrease the P-gp Multidrug Transporter Activity in Human Macrophages

— The problem of reduced effectiveness of antituberculosis drugs is currently associated not only with the development of drug resistance in the pathogen but also with the functional activity of the P-gp (P-glycoprotein) multidrug resistance protein of macroorganism cells. One of the main antituberculosis drugs, rifampicin (RIF), is a substrate for P-gp, which reduces its effectiveness. The article presents the data on the P-gp activity in proinflammatory human macrophages and assesses the effect of a new form of RIF encapsulated in lactic acid polymer nanoparticles, approved for medical use, on its activity. It was shown that THP-1 macrophages, in contrast to the THP-1 monocytes, are characterized by the functional activity increase of P-gp during differentiation as well as the preservation of the viability in the presence of RIF, which is associated with the P-gp activation. The new form of RIF is nontoxic to THP-1 monocytes and macrophages in comparison with the traditional form. When using the encapsulated form of RIF, the process of endocytosis/phagocytosis in macrophages is activated and the functional activity of P-gp decreases. The data obtained demonstrate that the development of encapsulated antituberculosis drugs, phagocytosis activators, which targetedly reduce the P-gp activity and thus affect the functional characteristics of human macrophages, seems to be a promising and relevant direction for increasing the effectiveness of antituberculosis drugs.