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Efficient brain uptake and distribution of an expanded CAG RNA inhibitor DB213 via intranasal administration. | LitMetric

AI Article Synopsis

Article Abstract

DB213 is an expanded CAG RNA inhibitor targeting polyglutamine diseases. This current study aims to investigate biopharmaceutic characteristics of DB213 as well as its brain uptake and distribution in C57 wild type mice, R6/2 Huntington's disease mice and Sprague-Dawley (SD) rats via intranasal administration. The biopharmaceutic characteristics of DB213 were investigated in vitro using Calu-3/MDCK/HEK293 cell lines and brain slices for its membrane transport, equilibrium dialysis for its plasma protein/brain tissue bindings and liver/brain microsomes incubation for its enzyme kinetics profiles. In vivo study of DB213 brain distribution was conducted in rats via intravenous and intranasal routes at 50 mg/kg followed by its brain uptake evaluation in mice at 25 mg/kg via intranasal route. In vitro membrane transport studies found that DB213 not only had a limited passive diffusion with a P value of 1.75 × 10 cm/s in Calu-3 cell monolayer model but also was substrate of MRP2, MRP3, and amino acid transporter. Furthermore, DB213 demonstrated higher binding towards brain homogenate (80%) than plasma (10%) with limited metabolism in liver and brain. After intranasal administration of DB213, both olfactory bulb and trigeminal nerve served as its entry points to reach brain as demonstrated in rats while efficient brain uptake was observed in mice. In summary, limited nasal epithelium permeability and MRP2/MRP3 mediated efflux transport of DB213 could be overcome by its influx transport via amino acid transporter and minimal liver and brain metabolism, which further contribute to its rapid brain uptake and distribution in mice and rats.

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http://dx.doi.org/10.1016/j.ejps.2018.10.025DOI Listing

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