Cidofovir transport in the pigmented rabbit conjunctiva.
OBJECTIVE
To characterize cidofovir (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine) transport in the pigmented rabbit conjunctiva and to evaluate the formulation influence on its transport.


METHODS
The excised pigmented rabbit conjunctiva was mounted in the modified Ussing chamber. Cidofovir transport was initiated by applying 3H-cidofovir to the donor compartment and assayed by measuring the radioactivity accumulated in the receiver fluid over 180 min.


RESULTS
Cidofovir flux in the mucosal-to-serosal direction increased proportionally with drug concentration over the 0.01 to 1 mM range. Cidofovir transport (0.01 mM) at 37 degrees C in the mucosal-to-serosal direction was not significantly different from that in the opposite direction or from that at 4 degrees C. Hypotonicity (80 mOsm/kg), 0.5% EDTA, and 0.0125% benzalkonium chloride increased the apparent permeability coefficient of cidofovir 3, 21, and 49 times, respectively. This was accompanied by a corresponding 43%, 86%, and 96% reduction in the transconjunctival electrical resistance over 180 min. The reduction in transepithelial electrical resistance elicited by hypotonicity was reversible. There was a good correlation between apparent permeability coefficient and the transconjunctival conductance, suggesting that cidofovir may undergo paracellular passive diffusion in the conjunctiva.


CONCLUSIONS
Cidofovir transport in the rabbit conjunctiva may be via paracellular passive diffusion. Formulation changes may improve cidofovir absorption from the conjunctival route.
Hosoya
K
K
Department of Pharmaceutical Sciences, University of Southern California, Los Angeles 90033, USA.
Lee
V H
VH
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001548:Benzalkonium Compounds / Q000494:pharmacology; D001692:Biological Transport; D000077404:Cidofovir; D003228:Conjunctiva / Q000378:metabolism*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004492:Edetic Acid / Q000494:pharmacology; D006982:Hypertonic Solutions / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D009994:Osmolar Concentration; D011817:Rabbits; D013696:Temperature
D000998:Antiviral Agents; D001548:Benzalkonium Compounds; D006982:Hypertonic Solutions; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D004492:Edetic Acid; D000077404:Cidofovir