RT Journal Article SR Electronic T1 Functional Characterization of Carrier-Mediated Transport of Pravastatin across the Blood-Retinal Barrier in Rats JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.115.066266 DO 10.1124/dmd.115.066266 A1 Shinobu Fujii A1 Chikako Setoguchi A1 Kouichi Kawazu A1 Ken-ichi Hosoya YR 2015 UL http://dmd.aspetjournals.org/content/early/2015/10/02/dmd.115.066266.abstract AB Systemically administered pravastatin effectively treats diabetic retinopathy without central nervous system side effects. The efflux transport mechanism of pravastatin from the brain has already been clarified. In this study, the influx of pravastatin across the blood-retinal and blood-brain barriers (BRB and BBB), as well as the efflux of pravastatin from the retina, were investigated using rats. Pravastatin influx (blood-to-tissues) was assessed using the retinal and brain uptake index (RUI and BUI) methods, and microdialysis was performed to investigate the efflux (retina-to-blood) transport of pravastatin. The RUI and BUI values for [3H]pravastatin were lower than those expected based on its lipophilicity, suggesting that the influx transport across the BRB and BBB was less than the reverse direction transport. The RUI and BUI values for [3H]pravastatin were significantly decreased by pravastatin, digoxin, and probenecid, indicating that pravastatin undergoes carrier-mediated influx transport in the blood-to-tissues direction across the BRB and BBB. Following intravitreal injection, [3H]pravastatin and the bulk flow marker [14C]D-mannitol were found to be eliminated bi-exponentially from the vitreous humor. The elimination rate constant of [3H]pravastatin during the terminal phase was 1.66-fold greater than that of [14C]D-mannitol. Efflux transport was reduced in the retinal presence of pravastatin, digoxin, and benzylpenicillin, suggesting that pravastatin is transported via efflux transporters. In conclusion, pravastatin is transported across the BRB via uptake and efflux transporters in both the blood-to-retina and retina-to-blood directions, and the retina-to-blood transporters are dominant, based on the lower values of the RUI compared with the values expected from the lipophilicity.