Recent advances in drug and nutrient transport across the blood-retinal barrier

ABSTRACT

Introduction: The blood-retinal barrier (BRB) is the barrier separating the blood and neural retina, and transport systems for low-weight molecules at the BRB are expected to be useful for developing drugs for the treatment of ocular neural disorders and maintaining a healthy retina.

Areas covered: This review discusses blood-to-retina and retina-to-blood transport of drugs and nutrients at the BRB. In particular, P-gp (ABCB1/MDR1) has low impact on the transport of cationic drugs at the BRB, suggesting a significant role of novel organic cation transporters in influx and efflux transport of lipophilic cationic drugs between blood and the retina. The transport of pravastatin at the BRB involves transporters including organic anion transporting polypeptide 1a4 (Oatp1a4). Recent studies have shown the involvement of solute carrier transporters in the blood-to-retina transport of nutrients including riboflavin, L-ornithine, β-alanine, and L-histidine, implying that dipeptide transport at the BRB is minimal.

Expert opinion: Novel organic cation transport systems and the elimination-dominant transport of pravastatin at the BRB are expected to be useful in systemic drug delivery to the neural retina without CNS side effects. The mechanism of nutrient transport at the BRB is expected to provide a new strategy for delivery of nutrient-mimetic drugs.

KEYWORDS:

• Blood-retinal barrier
• blood-brain barrier
• transporter
• drug delivery
• organic cation
• organic anion
• vitamin
• dipeptide

Article highlights

• The blood-retinal barrier (BRB) has two different barrier structures formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB) to regulate the transport of low-weight molecules between the blood and neural retina.

• Evidence suggests low influence of P-gp on the transport of cationic drugs at the BRB, clearly differentiating its barrier function from the blood-brain barrier.

• The blood-to-retina transport of cationic drugs at the BRB involves novel organic cation transporters, which is expected to be useful in systemic delivery of cationic neuroprotectants to the retina.

• The elimination of cations including endogenous compounds and neurotoxins across the BRB is suggested to involve retina-to-blood transport systems.

• Evidence suggests preferential retina-to-blood transport of pravastatin, which is likely to involve Oatp1a4, Oat3, MRP4, and BCRP localized on the luminal side of the inner BRB.

• Involvement of RFVTs, CAT1, TAUT, and LAT1 is suggested in the blood-to-retina transport of riboflavin, L-ornithine, β-alanine, and L-histidine, respectively across the inner BRB.

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Acknowledgments

We thank the Association for Research in Vision and Ophthalmology (ARVO), The American Society for Pharmacology and Experimental Therapeutics, and The Pharmaceutical Society of Japan for their kindness as the copyright holders.

Declaration of interest

Yoshiyuki Kubo was supported by the Japan Society for the Promotion of Science and the Takeda Science Foundation. Shin-ichi Akanuma was supported by the Japan Society for the Promotion of Science and Research Grants from the Smoking Research Foundation. Ken-ichi Hosoya was supported by the Japan Society for the Promotion of Science. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The present study was financially supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number JP16H05110 and JP17K08409), JSPS Core-to-Core Program (B. Asia-Africa Science Platforms), and Research Grants from the Smoking Research Foundation and the Takeda Science Foundation.