Perturbation of rat renal tubule transport of the organic cation amantadine in recent onset streptozotocin-induced diabetes and in uninephrectomy.
The effects of early-stage diabetes mellitus and uninephrectomy on the renal tubule transport of amantadine were investigated. Kidney tubules were isolated from streptozotocin-induced diabetic (+/- insulin treatment) uninephrectomized, and control male Sprague-Dawley rats. There were no differences in the Km of amantadine uptake in renal proximal and distal tubules for the imposed treatments compared with control values. Vmax for amantadine uptake in the proximal tubules of diabetic and uninephrectomized rats was higher than the respective control (P < 0.05). Vmax for insulin-treated diabetic rats was similar to control values but was lower than that for untreated diabetic rats (P < 0.05). Vmax for distal tubule uptake was not altered by any treatment. Structure-activity studies demonstrated that bicarbonate-dependent amantadine uptake was inhibited by glycolate and lactate, but not by propionate or alpha-, beta-, or gamma-hydroxybutyrate. Early stage streptozotocin-induced diabetes mellitus and uninephrectomy induced changes in the kidney that resulted in a similar selective increase in proximal tubule amantadine uptake. These data represent the first description that experimentally induced diabetes mellitus and uninephrectomy modulate the function of the renal tubule organic cation (amantadine) transport system. Both interventions represent potential models in which phenotypic modulation of the renal elimination of organic cationic drugs may be achieved and studied.
Goralski
K B
KB
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
Stupack
D G
DG
Hatch
G M
GM
Sitar
D S
DS
D000547:Amantadine / Q000493:pharmacokinetics*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D004734:Energy Metabolism / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007684:Kidney Tubules / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
D001639:Bicarbonates; D002352:Carrier Proteins; D015259:Dopamine Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D007773:Lactates; D000547:Amantadine