Renal tubular transport of a polar cardiac glycoside, ASI-222, in rats; Clearance and micropuncture studies

Using renal clearance and micropuncture techniques, the urinary excretion and tubular transport of an aminosugar cardenolide, [³H]ASI-222, was evaluated in anesthetized rats made diuretic by i.v. infusion of a fluid load. In the clearance experiments, 29.7 ± 2% of the filtered load of ASI-222 appeared in the urine. Fractional excretion of ASI-222 remained unaltered when the rats were treated with spironolactone or with spironolactone plus nonradioactive ASI-222 (500 μg/kg), although urine flow, glomerular filtration rate and the renal clearance of ASI-222 changed significantly. Tubular fluid samples obtained from early proximal convolutions contained 26.8 ± 1.7% of ASI-222 that would have entered the tubule by free filtration, suggesting that only about one-fourth of the substance in the glomerular blood is filterable. The percentage of ASI-222 present in the lumen of the nephron at late proximal and distal collection sites and at the ureter remained relatively constant and averaged 26.3 ± 1.4, 23.5 ± 3.8 and 24.4 ± 1.5%, respectively. Efflux of ASI-222 from the tubule did not occur even at a lumen to peritubular concentration ratio of 10 or greater. Reabsorption of the filtered water progressed along the nephron and only 2.6 ± 0.6% appeared in the final urine. Evidence for transtubular influx of ASI-222 was obtained after placement of the drug on the surface of the kidney, producing a high peritubular to luminal concentration gradient. The data indicate that one-fourth of ASI-222 entering the renal glomeruli is filtered, it remains in the tubular lumen and is subsequently excreted in the urine. Although the drug may enter the nephron across the tubular epithelium under special conditions, its net transtubular movement is negligible after systemic administration. In the rat, the renal elimination of this polar cardenolide depends on filtration and represents a fairly constant component of its overall physiological disposition.