RENAL TUBULAR TRANSPORT OF CIMETIDINE IN THE ISOLATED-PERFUSED KIDNEYOF THE RAT

The renal handling of cimetidine (pK(a) = 6.8) was studied in the isol ated perfused rat kidney (IPK). Concentrations in the therapeutic rang e (<10 mu g/ml) had little adverse effects on the functional parameter s of the IPK, and even a concentration of 250 mu g/ml still had only m inor effects. When initial perfusate concentrations were low (<2.5 mu g/ml), the ratio of renal clearance over filtered amount (CL(R)/GF) wa s similar to 3, indicating net tubular secretion. CL(R)/GF decreased a t increasing perfusate concentrations, and above 25 mu g/ml, there was progressive net reabsorption (CL(R)/GF < 1). CL(R)/GF was highly depe ndent on variations in urine flow and pH, which is indicative of subst antial tubular reabsorption by nonionic diffusion. A kinetic model was used to describe the renal handling of cimetidine. This model incorpo rates the variables influencing the clearance of cimetidine, like urin e flow, glomerular filtration rate, and urine pH. Cimetidine was subje ct to active tubular secretion following Michaelis-Menten kinetics and passive tubular reabsorption of the unionized fraction. The constant for reabsorption was 197 +/- 40 mu l/min, the Michaelis-Menten constan t for tubular secretion was 0.2 +/- 0.1 mu g/ ml, end the maximum tran sport capacity was 1.3 +/- 0.3 mu g/min. Cimetidine did not accumulate in IPK, with kidney to perfusate ratios of similar to 2. In conclusio n, the renal handling of cimetidine in the IPK is concentration-depend ent and is determined by glomerular filtration, active tubular secreti on, and a substantial flow- and pH-dependent passive reabsorption.