Role of P-Glycoprotein in the Distribution of the HIV Protease Inhibitor Atazanavir in the Brain and Male Genital Tract

The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluated in vitro in (i) Pglycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using an in situ single-pass intestinal perfusion model. Our data suggest that raltegravir is a substrate but not an inhibitor of the drug efflux transporters P-gp and BCRP. These transporters might play a role in the restriction of raltegravir permeability across the blood-brain, bloodtesticular, and blood-intestinal barriers, potentially contributing to its low tissue concentrations and/or low oral bioavailability observed in the clinic setting.

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The incidence of diseases is on the surge as exemplified by the recent occurrence in West Africa of Ebola Virus (EBOV) and increase of Zika Virus in Brazil. These pathogens have evolved strategies to evade the human immune system and thus continue to be globally important human pathogens. Bioengineering capabilities are on the increase with rapid advances in synthetic biology and allied technologies (nanobiotechnology, nanotechnology, OMICs technologies, and genetic engineering) which bring potential future prospects in combating disease causing agents using the knowledge of pathogenesis of these disease causing agents. This paper specifically takes a forward looking approach in proposing a potential future use of bioengineering technologies to combat disease causing pathogens as exemplified by Human Immunodeficiency Virus (HIV), Ebola Virus (EBOV), and Mycobacterium tuberculosis through the design, building and testing of synthetic bioengineered minimal genomes with pathogen neutralising capabilities and pathogen detection sensitivity similar to whole cell based biosensors.