Involvement of nucleoside transporters in the transcorneal permeation of topically instilled substrates in rabbits in-vivo

The objective of the current study was to characterize and evaluate the functional importance of the Nucleoside Transporters (NTs) in the cornea of the rabbits. Reverse transcriptase polymerase chain reaction (RT-PCR) was used for the molecular characterization of the NTs. Their functionality was evaluated using two substrates, ribavirin and cytarabine. Dipyridamole was used as a blocker for the study. All the treatments were given topically. Molecular characterization of NTs revealed presence of cnt1, cnt2, cnt3 and cnt3 in the cornea. The concentration vs time profile for cytarabine in Aqueous Humor (AH) exhibited a statistically significant (p < 0.05) drop at 1 h with blocker pretreatment. The mean AUC(0-2) between the treatments was also differing in a significant (p < 0.05) manner. The concentration vs time profile for ribavirin in AH also showed a significant (p < 0.05) decrease in its concentration at 1 h with blocker pretreatment. Dipyridamole was able to block ribavirin's entry with as low as 40 nM concentration while complete blockade was achieved at 8 mM and above. When cytarabine and ribavirin were co-administered, ribavirin at a concentration of 6.5 mM significantly inhibited (p < 0.05) the transcorneal permeation of cytarabine up to 80%. To conclude, this study showed the presence and functional importance of NTs in the transcorneal uptake of nucleoside substrates. This study further revealed the presence of concentration dependent competitive inhibition among substrates for their transcorneal permeation.