Renal tubular transport of cimetidine in the isolated perfused kidney of the rat.

The renal handling of cimetidine (pKa = 6.8) was studied in the isolated perfused rat kidney (IPK). Concentrations in the therapeutic range (< 10 micrograms/ml) had little adverse effects on the functional parameters of the IPK, and even a concentration of 250 micrograms/ml still had only minor effects. When initial perfusate concentrations were low (< 2.5 micrograms/ml), the ratio of renal clearance over filtered amount (CLR/GF) was approximately 3, indicating net tubular secretion. CLR/GF decreased at increasing perfusate concentrations, and above 25 micrograms/ml, there was progressive net reabsorption (CLR/GF < 1). CLR/GF was highly dependent on variations in urine flow and pH, which is indicative of substantial tubular reabsorption by nonionic diffusion. A kinetic model was used to describe the renal handling of cimetidine. This model incorporates the variables influencing the clearance of cimetidine, like urine flow, glomerular filtration rate, and urine pH. Cimetidine was subject to active tubular secretion following Michaelis-Menten kinetics and passive tubular reabsorption of the unionized fraction. The constant for reabsorption was 197 +/- 40 microliters/min, the Michaelis-Menten constant for tubular secretion was 0.2 +/- 0.1 microgram/ml, and the maximum transport capacity was 1.3 +/- 0.3 microgram/min. Cimetidine did not accumulate in IPK, with kidney to perfusate ratios of approximately 2. In conclusion, the renal handling of cimetidine in the IPK is concentration-dependent and is determined by glomerular filtration, active tubular secretion, and a substantial flow- and pH-dependent passive reabsorption.