Heterogeneity among beta-adrenoreceptor blockers in the modulation of energy-dependent uptake of the organic cation amantadine by rat renal tubules.
Eight representative beta-adrenoreceptor blocking drugs, acebutolol, atenolol, labetalol, metoprolol, nadolol, pindolol, propranolol, and timolol, were studied in vitro with respect to their potential to block energy-dependent uptake of [3H]amantadine into proximal and distal rat renal tubule fragments in the presence and absence of bicarbonate. Five of the eight beta-adrenoreceptor blockers showed a dose-dependent inhibition of renal tubule accumulation of amantadine: labetalol, metoprolol, pindolol, propranolol, and timolol. Labetalol was the only beta-adrenoreceptor blocker with greater inhibitory potency in phosphate-based buffer than in bicarbonate-based buffer. Propranolol was the most potent inhibitor of renal tubule amantadine accumulation with IC50 values of 15 +/- 10 and 31 +/- 11 microM for proximal and distal tubule fragments, respectively, in a bicarbonate-based buffer environment. Inhibition in a phosphate-based buffer was less potent only in proximal tubules, with an IC50 of 76 +/- 30 microM. Kinetic studies of propranolol inhibition of amantadine uptake were consistent with both uncompetitive and competitive inhibition mechanisms in bicarbonate-based buffer in both proximal and distal renal tubule segments. There was no chiral preference between the R and S forms of propranolol for the inhibitory effects observed. These data suggest that there is potential for selection among the beta-adrenoreceptor blocking drugs to minimize or restrict the inhibition of amantadine energy-dependent uptake at the organic cation ion uptake sites characterized by amantadine in the presence and absence of bicarbonate.
Stupack
D G
DG
Department of Pharmacology and Therapeutics, Faculty of Medicine, The University of Manitoba, Winnipeg, Canada.
Escobar
M R
MR
Carlisle
M
M
Davie
T
T
Sitar
D S
DS
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000547:Amantadine / Q000493:pharmacokinetics*; D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D001639:Bicarbonates; D000547:Amantadine