In both rat strains, P-gp operates in the blood-ocular barriers, and the impact of P-gp on BRB permeability to quinidine and verapamil is lower than that on BBB permeability.

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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 [ 3 H]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 H]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 H]pravastatin and the bulk flow marker ]pravastatin during the terminal phase was 1.66-fold greater than that of [ 14 C]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 IntroductionAlthough some statins have pharamacologic effects on diabetic retinopathy, as well as central nervous system (CNS) side effects, systemically administrated pravastatin reduces signs of diabetic retinopathy in diabetic patients and does not produce CNS side effects such as sleep disturbances (Gordon et al., 1991;Saheki et al., 1994).Generally, the permeability of drugs into the retina from the blood is strictly regulated by the blood-retinal barrier (BRB), which is analogous to the blood-brain barrier (BBB). The BRB consists of both retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial (RPE) cells (outer BRB), which together form the complex tight junctions that restrict paracellular solute transport. The control of the intraocular environment and the maintenance of neuroretinal homeostasis are mediated, in part, by the various transporters expressed at the BRB (Hosoya and Tomi, 2005).Pravastatin is a substrate of the organic anion transporting polypeptides1a4 (oatp2; slco1a4) and the organic anion transporter 3 (oat3; slc22a8) (Kikuchi et al., 2004). Oatp1a4 is localized to both the luminal and abluminal membranes of the inner BRB and on the apical membrane of RPE cells of rats (Akanuma et al., 2013), whereas oat3 is expressed on only the abluminal side of the rat inner BRB and is not found on RPE cells (Ho...

The combined effects of bucillamine (Buc) and etanercept (ETN) on a rat model of type II collagen (CII)-induced arthritis (CIA) after treatment onset were investigated. In the combination treatment, rats received Buc 30 mg/kg orally administered once daily from the onset of arthritis or from 4 days after the onset of arthritis and ETN 0.3 mg/kg subcutaneously administered once on the day of onset. The effects of monotherapy with Buc and ETN, respectively, and of Buc + ETN combination therapy on the resulting polyarthritis were evaluated by histopathological analyses and measurements of hindpaw volumes, serum anti-collagen antibody and immunoglobulin levels, and cytokine levels. The Buc + ETN therapeutic combination reduced hindpaw swelling, synovial proliferation, bone destruction, new bone formation, and inflammatory cell infiltration in CIA. Montherapy with Buc showed a tendency to ameliorate these symptoms, while monotherapy with ETN reduced hindpaw swelling at 4 days after administration but did not maintain treatment efficacy toward the end of the experimental period. Histopathological findings did not reveal any efficacy of the ETN therapy. ETN alone increased the serum immunoglobulin levels, while its combination with Buc reduced these levels. Similar results were obtained for serum anti-CII antibody titers. The Buc + ETN combination treatment also reduced serum interleuking (IL)-1alpha and granulocyte macrophage colony-stimulating factor and tended to reduce serum IL-1beta and IL-6 levels. These results suggest that a combination therapy of Buc and ETN may be effective for the treatment of rheumatoid arthritis (RA).