Kinetic studies on drug disposition in rabbits. I. Renal excretion of iodopyracet and sulfamethizole.

In order to quantify the renal handling of iodopyracet (IOD) and sulfamethizole (SMZ), single-drug clearance studies in rabbits were performed under quasi-steady state conditions with stepwise increasing the infusion rate of IOD or SMZ. Although concentration dependence of plasma protein binding was observed for both drugs, the urinary excretion rate of IOD was proportional to its total plasma concentration at low total plasma concentrations of 0.05-0.8 mM. On the other hand, the relationship between urinary excretion rate and total plasma concentration of SMZ was a concave-ascending curve at low plasma concentrations and the renal clearance of SMZ was sensitive to changes in plasma protein binding. However, renal clearances referenced to unbound plasma concentration at total plasma concentrations of 0.05 mM for IOD and SMZ were 9.5 and 38 l/h, respectively. Those values were much greater than the effective plasma flow in rabbits. These facts indicated that the intrinsic clearances at the sites of tubular secretion were high and that the rates of secretion were fully or partially limited by the renal plasma flow. Furthermore it was suggested that unbound drug was liberated from plasma protein at the sites of tubular secretion. The data obtained at high plasma concentrations indicated that the tubular secretion of IOD had capacity limited characteristics and that the urinary excretion of SMZ involved tubular reabsorption as well as saturable tubular secretion. From the data obtained, a perfusion-limited pharmacokinetic model was constructed characterizing the excretory processes, namely, glomerular filtration, passive tubular reabsorption, saturable tubular secretion and reequilibrium between bound and unbound drugs in plasma. For both drugs, the estimates for bulk flow rate were reasonable values of effective renal plasma flow and the dissociation constants for tubular secretion agreed well with those for in vitro renal cortex accumulation, suggesting that the kinetic model based on physiological concepts was useful for the understanding of the drug elimination processes.

[The renal transport of cardiotrast, verografin and iodamide]. / Pochechnyi transport kardiotrasta, verografina i iodamida.

In chronic experiments on dogs it was shown that verografin and iodamide are excreted from the body not only by filtration but by tubular excretion as well. The maximal transport of verografin and iodamide is significantly lower than that of cardiotrast. In experiments on rats similar results were obtained. Concurrent administration of verografin and iodamide with cardiotrast decreases their excretion in the urine in rats that is probably due to competition for the common transport system in the epithelium of renal tubules.

[Effect of taktivin on diuresis and tubular cardiotrast secretion in the kidney]. / Vliianie taktivina na mocheotdelenie i kanal'tsevuiu sekretsiiu kardiotrasta v pochke.

The effect of a new immunomodulator taktivin (7-20 micrograms/kg subcutaneously, for 6 days) on the diuresis and tubular transport of cardiotrast (diodrast) was studied on rats. taktivin was shown to increase the tubular transport of the xenobiotic without significant changes in glomerular filtration and renal excretion of water, sodium, potassium, uric acid and creatinine. Possible mechanism of taktivin's action on the tubular transport of xenobiotics is discussed.

Physiologically based pharmacokinetic model for the renal clearance of iodopyracet and the interaction with probenecid in the dog.

Plasma kinetics and renal excretion of iodopyracet (3.0 g, administered i.v.) with and without concomitant administration of probenecid were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid. A physiologically based kidney model is proposed comprising all the functional characteristics of the kidney that determine the excretion of iodopyracet, i.e. renal plasma flow, urine flow, protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. Renal clearance of iodopyracet is characterized by supply-limited elimination at low plasma concentrations and capacity-limited elimination at high plasma levels. The interaction with probenecid could be adequately described with the model by competitive inhibition of the carrier-mediated uptake of iodopyracet into the tubular cells. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of iodopyracet within the cells, which was clearly diminished in the presence of probenecid.