Determination of plasma and tissue distribution of 27-hydroxycholesterol after a single oral administration in a mouse model

Background: The side chain 27-hydroxycholesterol has been reported to inhibit the replication of several pathogen viruses, including herpes simplex virus, rhinovirus, rotavirus and SARS-CoV-2, in in vitro and ex vivo models. Objective: In view of a future potential therapeutic use of 27-hydroxycholesterol, a pilot pharmacokinetic study was set up. Methods This active substance was complexed with 2-hydroxypropyl-beta-cyclodextrin and orally administered in a single dose to CD1 male mice; its recovery in plasma and a few tissues up to 24 h post-treatment was evaluated. Results: The absorption of the oxysterol by the small intestine was moderate, due to its physicochemical properties, but still relevant and rapid, showing a peak at 1 h after supplementation and being almost completed 24 h after treatment. 27-Hydroxycholesterol appeared to be a high hepatic extraction drug, possibly with an extrahepatic component contributing to the total clearance. Conclusions: Following the oral 25 mg/kg dosing, plasma levels of 27-hydroxycholesterol showed an average steady-state concentration similar to that shown to be able to inhibit the replication of all viruses tested so far in in vitro models. Significance statement The first pharmacokinetic data relative to a natural oxysterol administered p.o. are reported. Data should contribute to further elucidate oxysterol pathophysiology and guide non-clinical studies aiming at investigating possible therapeutic use of 27-hydroxycholesterol or its analogs.