The effect of lactate on sex differences in rat renal tubular energy-dependent transport of the organic cation amantadine.
The purpose of this study was to determine if the inhibitory effect of lactate on the tubular transport of amantadine would extend to a demonstrable sex difference between male and female rats. Enriched fractions of renal proximal and distal tubules were incubated with [(3)H]-amantadine in the presence and absence of racemic lactate. Lactate buffer unmasked a sex difference in proximal tubular transport capacity. Compared to bicarbonate, lactate also decreased the affinity for amantadine uptake by both proximal and distal tubule fragments in both male and female rats. No difference occurred between male and female rats in terms of the inhibitory constant (K(i)) for lactate. These data suggest that female rats have decreased amantadine transport efficiency and potentially increased susceptibility to amantadine toxicity due to transport inhibition by lactate. Our data may help to explain the mechanism for increased amantadine toxicity observed in elderly female patients.
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Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada.
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D000547:Amantadine / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002021:Buffers; D005260:Female; D006801:Humans; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D019344:Lactic Acid / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics
D000998:Antiviral Agents; D002021:Buffers; D019344:Lactic Acid; D000547:Amantadine