TY - JOUR
T1 - Functional characterization of carrier-mediated transport of pravastatin across the blood-retinal barrier in rats
AU - Fujii, Shinobu
AU - Setoguchi, Chikako
AU - Kawazu, Kouichi
AU - Hosoya, Ken Ichi
N1 - Publisher Copyright:
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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 bloodretinal and blood-brain barriers (BRB and BBB) and 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 reversedirection transport. The RUI and BUI values for [3]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. After intravitreal injection, [3]pravastatin and the bulk flow marker [14C]D-mannitol were found to be eliminated biexponentially from the vitreous humor. The elimination rate constant of [3]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.
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 bloodretinal and blood-brain barriers (BRB and BBB) and 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 reversedirection transport. The RUI and BUI values for [3]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. After intravitreal injection, [3]pravastatin and the bulk flow marker [14C]D-mannitol were found to be eliminated biexponentially from the vitreous humor. The elimination rate constant of [3]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.
UR - http://www.scopus.com/inward/record.url?scp=84948956533&partnerID=8YFLogxK
U2 - 10.1124/dmd.115.066266
DO - 10.1124/dmd.115.066266
M3 - 学術論文
C2 - 26431714
AN - SCOPUS:84948956533
SN - 0090-9556
VL - 43
SP - 1956
EP - 1959
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 12
ER -
