Disposition characteristics of protein drugs in the perfused rat kidney.

The renal disposition characteristics of 111In-labeled neocarzinostatin (NCS), soybean trypsin inhibitor (STI), and superoxide dismutase (SOD) were studied in the perfused rat kidney. In a single-pass indicator dilution experiment, venous and urinary recovery profiles and tissue accumulation of proteins were determined under filtering or nonfiltering conditions. In the nonfiltering kidney perfusion experiment, no significant tissue accumulation was observed, suggesting minimal uptake from the glomerular and peritubular capillary sides. Therefore, tissue recovery corresponded to that with tubular reabsorption after glomerular filtration. The total amount of NCS or STI being filtrated through glomeruli, the sum of tissue and urinary recoveries, was similar to that of inulin, but that of SOD was about half. Similarly, the steady-state distribution volumes (Vd) of NCS and STI obtained by moment analysis of their venous outflow curves were similar to that of inulin, while the Vd value of SOD was significantly lower. These results suggest the restricted passage of SOD through the glomerular and postglomerular capillary wall. The tubular reabsorption ratio of proteins against the total filtrated amount decreased with an increase in the administered dose, suggesting nonlinearity of reabsorption. SOD had the largest reabsorption ratio. Thus, this experimental system is useful for quantitative analysis of renal disposition of proteins.

Mechanism of accumulation of the antitumor protein antibiotic neocarzinostatin in bladder tissue: intravenous administration, urinary excretion, and absorption into bladder tissue.

Some aspects of the absorption, distribution, and excretion of neocarzinostatin (NCS), a proteinous antitumor antibiotic, were studied in rabbits. NCS was given intravenously (i.v.) via the auricular vein, or [(14)C]NCS was instilled directly into the cavity of the bladder by tubing. In both groups, ureterostomy was performed, so that the drug excreted in the urine did not pass through the bladder. The results showed extremely rapid renal clearance; namely, two-thirds of the total recovered was excreted in the first 5 min. It was also shown that drug infused into the bladder cavity could be recovered in urine from the ureterostomized ureter. Also, the level of biological activity of NCS in bladder tissues after i.v. administration is significantly lower when ureterostomy is performed. Thus, evidence is presented for the absorption of NCS into bladder tissue from the lumen of the bladder. The high levels of NCS in bladder tissue are due to this effect as well as to accumulation via the iliac artery. These data should encourage further trials of NCS in bladder cancer. A study of urine containing NCS derived from i.v. administration showed an increase in antibacterial activity upon incubation, followed by a decrease. These effects are probably due to proteolysis, as shown by the appearance of a low-molecular-weight fragment and by the absence of such an increase in the presence of inhibitors of proteolysis.