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Rapid CommunicationShort Communication

Functional Characterization of Carrier-Mediated Transport of Pravastatin across the Blood-Retinal Barrier in Rats

Shinobu Fujii, Chikako Setoguchi, Kouichi Kawazu and Ken-ichi Hosoya
Drug Metabolism and Disposition December 2015, 43 (12) 1956-1959; DOI: https://doi.org/10.1124/dmd.115.066266
Shinobu Fujii
Nara Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma, Nara, Japan (S.F., C.S., K.K.); Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (S.F., K.H.)
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Chikako Setoguchi
Nara Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma, Nara, Japan (S.F., C.S., K.K.); Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (S.F., K.H.)
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Kouichi Kawazu
Nara Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma, Nara, Japan (S.F., C.S., K.K.); Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (S.F., K.H.)
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Ken-ichi Hosoya
Nara Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma, Nara, Japan (S.F., C.S., K.K.); Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (S.F., K.H.)
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Abstract

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) 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 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. After intravitreal injection, [3H]pravastatin and the bulk flow marker [14C]d-mannitol were found to be eliminated biexponentially 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

Footnotes

    • Received July 9, 2015.
    • Accepted October 1, 2015.
  • dx.doi.org/10.1124/dmd.115.066266.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (12)
Drug Metabolism and Disposition
Vol. 43, Issue 12
1 Dec 2015
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Rapid CommunicationShort Communication

Carrier-Mediated Transport of Pravastatin Across the BRB

Shinobu Fujii, Chikako Setoguchi, Kouichi Kawazu and Ken-ichi Hosoya
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1956-1959; DOI: https://doi.org/10.1124/dmd.115.066266

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Rapid CommunicationShort Communication

Carrier-Mediated Transport of Pravastatin Across the BRB

Shinobu Fujii, Chikako Setoguchi, Kouichi Kawazu and Ken-ichi Hosoya
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1956-1959; DOI: https://doi.org/10.1124/dmd.115.066266
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