A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog.

Ranitidine renal clearance was investigated in the beagle dog with or without concomitant infusion of cimetidine or probenecid. Ranitidine was excreted mainly by renal tubular secretion. Plasma clearance was reduced by probenecid from 198 +/- 47 to 119 +/- 41 mL min-1 (mean +/- SD.); renal clearance was reduced from 104 +/- 33 to 54 +/- 24 mL min-1 (p < 0.02) by probenecid and to 89 +/- 37 mL min-1 (NS) by cimetidine. Plasma and urine data were analysed simultaneously with a physiologically based kidney model and were both described adequately by the model, although tubular secretion could not be fully characterized as no saturation was achieved despite high dosages. Tubular secretion of ranitidine was simplified to first-order brush-border and basolateral transport across the proximal tubular cell. Basolateral transport was reduced (from 18.4 +/- 7.8 to 13.6 +/- 10.3 min-1 by cimetidine and 3.9 +/- 3.1 min-1 by probenecid), whereas no effect on brush-border exit was found. Estimated inhibition constants of cimetidine and probenecid were 62 and 4 micrograms mL-1, respectively. Summarizing, ranitidine renal pharmacokinetics were accurately described by the physiologically based kidney model presented in this paper. Model calculations suggest that interaction with cimetidine and probenecid results from competition for basolateral ranitidine uptake into tubular cells.

Saturable urinary excretion kinetics of famotidine in the dog.

An important elimination route of the histamine H2 antagonist famotidine is active tubular secretion via the renal organic cation transport system. To characterize the excretion kinetics of famotidine in-vivo, the relationship between plasma concentration and urinary excretion rate was investigated in the beagle dog over a wide concentration range. The maximum transport capacity and the apparent Michaelis-Menten constant of tubular secretion were estimated. Concentration-dependent renal clearance was determined either after intravenous infusion of high doses of famotidine for a short time or during continuous infusion. From individual experiments only indications of saturation were observed; these could not be quantified. A tubular titration curve, in which the active tubular famotidine secretion was plotted against the plasma concentration, was constructed from the data from all the experiments. Active tubular secretion was calculated for each experiment separately by subtracting the famotidine filtration rate from the total excretion rate. A tubular transport maximum of 2400 +/- 220 micrograms min-1 and an apparent Michaelis-Menten constant for tubular secretion of 26 +/- 4 micrograms mL-1 (76 +/- 12 microM) were estimated from the curve. To the best of our knowledge, this is the first time that saturation of famotidine renal clearance has been fully quantified in-vivo. Considering the low therapeutic plasma concentrations of famotidine (< 0.1 microgram mL-1), these results suggest that clinically the drug has a low interactive potential.

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.

Cimetidine uptake and interactions with cationic drugs in freshly isolated proximal tubular cells of the rat.

The uptake of cimetidine was investigated in freshly isolated proximal tubular cells of the rat as well as its interaction with other cationic drugs. The time-dependent uptake of 5 microM cimetidine was linear for 2 min and reached equilibrium after 10 min. The uptake was reduced at 4 degrees C or by addition of 5 mM mepiperphenidol. At pH 7.4, only a small percentage (20%) of cimetidine is present in the cationic form, which is thought to be necessary for transport by the organic cation transporter. At a more acidic pH 6.5, this percentage is increased to 67%, but there was no influence on the cellular uptake in comparison with control. The cationic form of cimetidine does not seem to be a prerequisite for the organic cation transporter in these cells. The uptake of cimetidine was concentration-dependent and saturable. The mepiperphenidol-sensitive uptake had a high (H) and low (L) affinity apparent Km,H of 6.7 +/- 1.2 microM and Km,L of 0.61 +/- 0.16 mM, and Vmax,H of 35.8 +/- 2.2 pmol/mg of protein.min and Vmax,L of 4.5 +/- 0.3 nmol/mg of protein.min. The concentration-dependent inhibition of other cationic drugs on 1 microM cimetidine uptake was investigated. The log concentration-inhibition curves of mepiperphenidol, famotidine and trimethoprim showed a high and low affinity IC50 value, with a potency ranking of mepiperphenidol = famotidine > trimethoprim. The other compounds had only a low affinity IC50 value and the inhibitory potency ranking was as follows: ranitidine = nizatidine > tetraethylammonium > probenecid.

Renal tubular excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine in the dog.

To investigate whether dogs are able to excrete acetylated drugs by active transport, the plasma kinetics and renal excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine were studied in the beagle dog after a rapid intravenous bolus injection. Two doses of N4-acetylsulphasomidine (1050 and 105 mg) and one dose of N4-acetylsulphadimethoxine (472 mg) were administered on separate occasions. The renal clearance (CLR) was as follows: N4-acetylsulphasomidine (1050 mg) 34 mL min-1; N4-acetylsulphasomidine (105 mg) 28 mL min-1; and N4-acetylsulphadimethoxine (472 mg) 24 mL min-1. CLR was higher than expected on the basis of the measured glomerular filtration rate, indicating that the N4-acetyl metabolites may be excreted by the renal tubules by active tubular transport. Saturation of the excretion process of N4-acetylsulphasomidine occurred with a transport maximum of 930 +/- 190 micrograms min-1 and a Michaelis-Menten constant of 37 +/- 10 micrograms mL-1. It may be concluded that the dog renal organic anion transport system is able to secrete acetylated sulphonamides.

Organic cation transport and cationic drug interactions in freshly isolated proximal tubular cells of the rat.

Freshly isolated proximal tubular cells (PTC) of the rat are used to study the uptake of a prototypical organic cation, tetraethylammonium (TEA), and the influence of other cationic drugs on TEA uptake. The time dependency of 50 microM TEA uptake was determined by incubating PTC for time periods from 10 sec until 60 min. TEA uptake was linear for at least 2 min and reached equilibrium after 30 min. The cell to medium ratio reached a value of 8 after 60 min, indicating marked accumulation of TEA. TEA uptake was concentration dependent and saturable, with an apparent Km of 63 +/- 7 microM and Vmax of 0.57 +/- 0.02 nmol/mg protein.min. In comparison with cells cultured on filters, the overall transport characteristics of TEA in PTC seem to resemble basolateral to apical flux. The concentration-dependent inhibition of some H2 antagonists and various cations on 32 microM TEA uptake was investigated, as well as the interaction with probenecid. Analysis of the log-concentration inhibition curves showed that mepiperphenidol, trimethoprim, famotidine and cimetidine had a high and low IC50 value, whereas ranitidine, nizatidine, cimetidine sulfoxide, N1-methylnicotinamide and probenecid had only a low IC50 value. The data reported here are comparable with those from other preparations, and it is possible to extrapolate to the human in vivo situation. Moreover, the isolation procedure is relatively simple and quick and the yield is high.