Functional expression of a sodium dependent nucleoside transporter on rabbit cornea: Role in corneal permeation of acyclovir and idoxuridine.
OBJECTIVE
The major objectives were to investigate functional expression of nucleoside transporters on the rabbit cornea and to delineate mechanism of corneal permeation of acyclovir (ACV) and idoxuridine (IDU). Methods. Transport studies were conducted with isolated rabbit corneas at 34 degrees C using [(3)H]thymidine, [(3)H]ACV and [(3)H]IDU.


RESULTS
Thymidine transport across rabbit cornea comprised of saturable (K(m) = 14.9 +/- 9.7 microM and V(max) = 0.045 +/- 0.0087 nmol/min) and non saturable (k(d) = 0.00015 +/- 0.000013 microl/min) components. Both purine and pyrimidine nucleosides including inosine inhibited transport of [(3)H]thymidine. However, nucleobases adenine and thymine did not have any inhibitory effect on thymidine transport which was sodium dependent with a Na(+): thymidine coupling ratio of greater than 1 : 1 indicating that the nucleoside transporter is of the N3 type. Although IDU inhibited transport of [(3)H]thymidine, unlabeled IDU and thymidine did not inhibit [(3)H]IDU transport suggesting that IDU was binding to the transporter but was not translocated by it. ACV did not affect transport of [(3)H]thymidine. Moreover, thymidine, adenine or unlabeled ACV did not inhibit [(3)H]ACV transport. Permeability coefficients of ACV and IDU over a 4 fold concentration range did not show any significant difference confirming that these antiviral agents permeate the cornea by passive diffusional mechanism.


CONCLUSIONS
Functional expression of a N3 type sodium dependent nucleoside transporter has been demonstrated on the rabbit cornea. Antiviral nucleoside analogs ACV and IDU are not substrates for this transporter and appear to permeate the cornea by simple passive diffusion.
Majumdar
Soumyajit
S
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.
Gunda
Sriram
S
Mitra
Ashim
A
D000212:Acyclovir / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D003315:Cornea / Q000378:metabolism*; D007065:Idoxuridine / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D033703:Nucleoside Transport Proteins / Q000378:metabolism*; D009705:Nucleosides / Q000494:pharmacology; D009994:Osmolar Concentration; D010042:Ouabain / Q000494:pharmacology; D010539:Permeability; D011817:Rabbits; D012964:Sodium / Q000378:metabolism* / Q000494:pharmacology; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013936:Thymidine / Q000493:pharmacokinetics
D000998:Antiviral Agents; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D013868:Thioinosine; D010042:Ouabain; D012964:Sodium; C001789:4-nitrobenzylthioinosine; D007065:Idoxuridine; D013936:Thymidine; D000212:Acyclovir