Carrier-mediated transport of monocarboxylate drugs in the pigmented rabbit conjunctiva.
OBJECTIVE
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 (Isc) and 14C-L.-lactate transport.


RESULTS
When added to the mucosal side at 37 degrees C and at pH 7.4, applications of as much as 40 mM L- and D-lactate increased Isc in a saturable manner. By contrast, no change in Isc was observed at 4 degrees 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
An Na+-dependent monocarboxylate transport process that may be used by non-steroidal 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.
Horibe
Y
Y
Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles 90033, USA.
Hosoya
K
K
Kim
K J
KJ
Lee
V H
VH
D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D001692:Biological Transport / Q000502:physiology; D002264:Carboxylic Acids / Q000493:pharmacokinetics*; D003228:Conjunctiva / Q000378:metabolism*; D004337:Drug Carriers; D024841:Fluoroquinolones; D019344:Lactic Acid / Q000493:pharmacokinetics; D008297:Male; D008564:Membrane Potentials; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics*; D011817:Rabbits; D012964:Sodium / Q000494:pharmacology*; D013379:Substrate Specificity
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002264:Carboxylic Acids; D004337:Drug Carriers; D024841:Fluoroquinolones; D009883:Ophthalmic Solutions; D019344:Lactic Acid; D012964:Sodium