The identification of a novel renal organic cation transport process, implications for drug interactions and altered renal drug elimination

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Goralski, Kerry Brennan
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The mechanisms that mediate and factors that modulate amantadine transport in isolated renal tubules have been previously characterized. However, amantadine may describe a different organic cation transport system compared to that described by the prototypical organic cation substrate tetraethylammonium (TEA). We performed amantadine and TEA uptake and efflux studies using isolated rat renal proximal and distal tubules. The kinetic data indicate the presence of two sites or amantadine and TEA uptake across the basolateral membrane. The major difference in mechanism was that amantadine uptake was bicarbonate-dependent whereas TEA uptake was not. Inhibition and efflux studies confirmed that amantadine and TEA identify disparate transporters. From these data we proposed that basolateral organic cation transporters be classified as amantadine-selective and TEA-selective. TEA does not interact and is not transported by the amantadine-selective transporters whereas amantadine can interact with the TEA-selective transporters but is not significantly transported by them. Furthermore inhibition studies using substrates or inhibitors of the cloned rat organic cation transporters rOCT1 and rOCT2 indicate that TEA transport into isolated rat renal tubules reflects transport by rOCT1 and rOCT2 whereas amantadine, transport reflects neither rOCT1 nor rOCT2. These data suggest that rOCT1 and rOCT2 are insufficient in describing renal tubule organic cation transport in its entirety. The remaining experiments focused on further characterizing the bicarbonate-dependent amantadine transporter under potential pathological conditions and in vivo. The effects of early-stage diabetes and uninephrectomy on renal tubule uptake of amantadine were investigated. It was determined that early-stage streptozotocin-induced diabetes and uninephrectomy induce changes in the kidney that result in a similar selective increase in bicarbonate-dependent amantadine uptake in the proximal tubule. We investigated the effects of NH4+ on the renal tubule energy-dependent uptake of the organic cation amantadine into isolated renal proximal and distal tubules from male and female rats. With some variation, NH4+ inhibited the energy-dependent uptake of amantadine into renal proximal and distal tubules of males and female rats. These data indicate that NH4+ may have a role in modulating access of organic cation drugs to the renal tubular organic cation transport systems. In vivo studies were carried out to address the effect of bicarbonate on the renal clearance and urinary excretion of amantadine. The major finding of this study was that an acute increase in plasma bicarbonate substantially decreased amantadine clearance. (Abstract shortened by UMI.)