Carrier-mediated transport of monocarboxylate drugs in the pigmented rabbit conjunctiva

PURPOSE. To determine whether an Na⁺-dependent monocarboxylate transport process exists on the mucosal side of the pigmented rabbit conjunctiva and to evaluate how it may contribute to the absorption of ophthalmic monocarboxylate drugs. METHODS. L-Lactate was used as a model substrate. The excised pigmented rabbit conjunctiva was mounted in a modified Ussing chamber for the measurement of short-circuit current (I(sc)) and ¹⁴C-L-lactate transport. RESULTS. When added to the mucosal side at 37°C and at pH 7.4, applications of as much as 40 mM L- and D-lactate increased I(sc) in a saturable manner. By contrast, no change in I(sc) was observed at 4°C or under the mucosal Na⁺-free condition. ¹⁴C-L-Lactate transport in the mucosal-to-serosal (m-s) direction at 0.01 mM revealed directionality, temperature dependency, Na⁺ dependency, and ouabain sensitivity, but not pH dependency. L-Lactate transport in the m-s direction consisted of a saturable Na⁺-dependent process by the transcellular pathway and a nonsaturable process by the paracellular pathway. For the saturable process, the apparent Michaelis-Menten constant was 1.9 mM, the maximum flux was 8.9 nanomoles/cm² per hour, and the apparent Na⁺:L-lactate coupling ratio was 2:1. ¹⁴C-L- Lactate transport in the m-s direction was significantly inhibited (46% to 83%) by the mucosal presence of various monocarboxylate compounds, but not by dicarboxylate compounds, zwitterionic compound, D-glucose, amino acids, and peptidomimetic antibiotics. Monocarboxylate nonsteroidal anti-inflammatory drugs and the antibacterial fluoroquinolones inhibited ¹⁴C-L-lactate transport by 40% to 85%, whereas prostaglandins and cromolyn had no effect. CONCLUSIONS. All Na⁺-dependent monocarboxylate transport process that may be used by nonsteroidal anti-inflammatory and fluoroquinolone antibacterial drugs for transport appears to be present on the mucosal side of the pigmented rabbit conjunctiva. A possible physiologic role for the Na⁺- dependent monocarboxylate transport process may be to salvage tear lactate.