In vivo analysis of amantadine renal clearance in the uninephrectomized rat: Functional significance of in vitro bicarbonate-dependent amantadine renal tubule transport

Amantadine transport into renal proximal and distal tubules is bicarbonate dependent. In the present study, we addressed the effects of bicarbonate on renal clearance and urinary excretion of amantadine. Renal clearance of ky nurenic acid was also studied to determine whether bicarbonate effects are specific for organic base transport by the kidney. After a moderate diuresi s was established, animals received i.v. [H-3]amantadine or [H-3]kynurenic acid followed by an acute dose of sodium bicarbonate or physiological salin e. Urine and blood samples were analyzed for [H-3]amantadine or [H-3]kynure nic acid, blood gases, and pH. Amantadine and kynurenic acid were excreted by the kidneys, and both compounds underwent renal tubular secretion. Amant adine metabolism occurred, and one metabolite was detected in the urine. In the bicarbonate-treated rats, the total amount of amantadine excreted in t he urine was decreased, whereas the amount of metabolite recovered was simi lar in both groups. Bicarbonate treatment caused a sustained increase in bl ood bicarbonate levels, a mild increase in blood pH, and a decrease in aman tadine renal clearance and in the amantadine/creatinine clearance ratio. On ly a transient decrease in the renal clearance of kynurenic acid and the ky nurenic acid/creatinine clearance ratio was observed. This study demonstrat es that short-term changes in bicarbonate concentration may have significan t effects on renal organic cation elimination. Coupled with our previous in vitro demonstration of bicarbonate-dependent organic cation transport, the present study suggests that bicarbonate inhibition of renal tubule organic cation secretion may explain the previous observation that bicarbonate dos ing decreases amantadine excretion by the kidney.