Decrease in In Vivo Efflux Transport via P-glycoprotein at the Rat Inner Blood-Retinal Barrier by Peripheral Administration of Lipopolysaccharide.

Purpose: This study aimed to determine in vivo alterations in the rat retinal distribution of a substrate for P-glycoprotein (P-gp), which restricts drug transport to the retina at the inner blood-retinal barrier (BRB), by peripheral administration of lipopolysaccharide (LPS), an inflammatory agent.

Methods: Using retinal capillaries isolated from rats 24 h after peripheral 5 mg/kg LPS administration, transport analyses with a fluorescent substrate of P-gp were performed. In vivo retinal distribution of [³H]digoxin, a P-gp substrate, in the LPS-administered rats was evaluated after intravenous or intracarotid artery injection. The mRNA and protein expression levels of P-gp in the retinal capillaries were evaluated.

Results: P-gp-mediated luminal transport of the fluorescent substrate was significantly attenuated in retinal capillaries of the LPS-administered rats. Moreover, in vivo retinal [³H]digoxin distribution in LPS-injected rats was significantly greater than that in saline-injected rats. Since the retinal distribution of [³H]D-mannitol, a paracellular transport marker, was not significantly altered in LPS-treated rats, it is suggested that in vivo elevation of retinal [³H]digoxin distribution is caused by P-gp downregulation at the inner BRB, but not a change in paracellular transport in the barrier. In retinal capillaries isolated from LPS-administered rats, expression analyses of P-gp mRNAs and protein indicated a reduction in its expression on the luminal membrane of the inner BRB.

Conclusion: Our study demonstrated that in vivo retinal distribution of P-gp substrates was elevated in LPS-administered rats via a decrease in the function and expression of P-gp at the inner BRB.