L(-LACTATE AND D(-)-LACTATE MODULATE RAT RENAL TUBULAR ACCUMULATION OF AMANTADINE IN THE PRESENCE AND ABSENCE OF BICARBONATE())

The effect of L(+)-, D(-)- and racemic (DL)-lactate on the energy-depe ndent renal uptake of the achiral organic cation amantadine was determ ined with purified proximal and distal cortical tubule fragments isola ted from rat kidneys. Kinetic parameters for uptake of amantadine were measured, under constant pH, in bicarbonate buffer (Krebs-Henseleit [ KHS]), and in lactate buffers (5 mM) with different proportions of the enantiomers. K-m for amantadine uptake increased in all lactate buffe rs compared with KHS for both proximal and distal tubules. K-m for upt ake in DL-lactate was similar to that in D(-)-lactate for proximal tub ules and to L(+)-lactate in distal tubules, but K-m in L(+)-lactate wa s higher than in D(-)-lactate for both tubules. Maximal transport capa city (V-max) in DL-lactate and mixtures of enantiomers were similar to KHS but higher than in pure L(+)and D(-)-lactate. In KHS, lactate inh ibited energy-dependent amantadine uptake in a biphasic manner. Graded competitive inhibition of amantadine uptake was observed between I an d 15 mM lactate for both proximal and distal tubules. This first phase (1-15 mM) inhibited 60% of amantadine uptake. The second phase (15-20 mM lactate) showed a much steeper slope and inhibited the remaining a mantadine uptake. There were no differences in inhibitory potencies of the lactate enantiomers for either proximal tubules or distal tubules amantadine tubule uptake. Our present studies suggest that L(+)- and D(-)-lactate modulate amantadine transport by interacting directly wit h the bicarbonate-dependent transport mechanism(s).