Site-selective effect of bicarbonate on amantadine renal transport: quinine-sensitive in proximal vs quinidine-sensitive sites in distal tubules.
The mechanism for bicarbonate enhancement of amantadine (A+) uptake was studied further. A selective modulatory effect of bicarbonate on the stereoselectivity of inhibition of A+ uptake by the stereoisomers, quinine (Q) and quinidine (QD), as reflected by the reversal of potency (Q > QD in KHS vs. QD > Q in phosphate), is reported. Studies were performed in bicarbonate (KHS) and phosphate buffers using purified cortical proximal (PT) and distal tubules (DT) from rat kidneys. Variations of extracellular K+ and Ca++ were used to assess the effect of membrane depolarization and calcium on A+ uptake by the tubules. K+ concentration manipulation (1.5-100 mM) did not change A+ uptake by PT or DT in KHS buffer. High Ca++ (5.0 mM) decreased A+ uptake by PT in KHS (P < .001), whereas in phosphate buffer, both 2.5 and 5.0 mM Ca++ decreased uptake (P < .001). In DT, 0.25 mM Ca++ enhanced A+ uptake (P < .05) in KHS, but 2.5 and 5.0 mM Ca++ decreased it in both buffers. Inhibition studies with Q and QD were performed to characterize the bicarbonate-dependent and bicarbonate-independent A+ transport sites further. Stereoselectivity of inhibition was observed in PT in all buffers used. Potency of Q was higher than QD in KHS but lower than QD in phosphate-buffered PT. QD potency remained unchanged. In phosphate-plus-bicarbonate-buffered PT, the inhibitory potencies for Q and QD increased, with the potency of QD being greater than in KHS (P < .001). For DT, Q and QD were equipotent in all buffers used.(ABSTRACT TRUNCATED AT 250 WORDS)
Escobar
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MR
Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Canada.
Sitar
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D000547:Amantadine / Q000493:pharmacokinetics*; D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D066298:In Vitro Techniques; D017136:Ion Transport; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D011188:Potassium / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats
D001639:Bicarbonates; D000547:Amantadine; D011802:Quinidine; D011188:Potassium; D002118:Calcium