The disposition characteristics of salicylic acid (SA) were investigated in analbuminemic rats after intravenous bolus injection of 10 and 173 mg kg-1 of SA to study the effects of plasma protein binding on drug disposition. Following the administration of 10 mg kg-1 of SA, total body SA clearance (CL) was markedly faster and its apparent volume of distribution (Vd) significantly greater in the analbuminemic rats in comparison to the controls. Further, the apparent elimination rate constant (kj) was two-fold greater and the corresponding elimination half-life (t 1/2) shorter in the rats with low plasma albumin. Whole body autoradiograms obtained following the administration of 14C-salicylic acid demonstrated that the tissue distribution of SA was greater in the analbuminemic rats which was in agreement with the larger Vd observed in this group of rats. After the administration of 173 mg kg-1 of SA, no differences in CL, Vd, kk or t 1/2 were noted between the analbuminemic and control rats. Dose-dependent SA disposition was observed in both the analbuminemic and control rats with the effects being more pronounced in the rats with low plasma albumin. The results suggested that the disposition characteristics of SA were markedly altered in the presence of low plasma albumin concentrations due to reduced plasma SA protein binding.

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PubMedDate not supplied

Crescentic glomerulonephritis associated with renal cell carcinoma after cancer immunotherapy.

A 59 year-old woman showed rapidly progressive glomerulonephritis during immunotherapy for metastatic renal cell carcinoma. She received unilateral nephrectomy and cytotoxic T lymphocyte (CTL) therapy for the treatment of retroperitoneal lymph node metastasis of renal cell carcinoma. With CTL therapy, her retroperitoneal lymph node mass decreased in size. One year after the third round of CTL therapy, her serum creatinine was increased and massive proteinuria occurred. Her renal biopsy specimen revealed necrotizing and crescentic glomerulonephritis with immune complex deposition. Her retroperitoneal lymph node mass continued to decrease in size. Consequently, for the purpose of avoiding interfering with the CTL therapy, we performed double filtration plasmapheresis (DFPP) monotherapy for removal of immune complexes without using immunosuppressive drugs or prednisolone. After 24 sessions of DFPP, her serum IgG was reduced from 3,942 mg/dL to 2,400 mg/dL, and proteinuria (from 9.0 g/day to 0.9 g/day) and renal function (serum creatinine; from 5.6 mg/dL to 2.2 mg/dL) also improved. However, 3 months after the final DFPP, she expired due to perforation of the colon. The autopsy sample of the kidney showed that most of the glomeruli were obsolescent, but immunoglobulin depositions were reduced and necrotizing lesions were diminished. In the patients with RPGN associated with renal cell carcinoma, renal functional recovery has not been observed upon immunosuppressive treatment. Consequently, plasmapheresis is considered to be one of the effective and safe methods for patients with this association. We also discuss previous reports of RPGN associated with renal cell carcinoma, or RPGN after cancer immunotherapy.

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PubMedDate not supplied

Hypoglycemic action and disposition of gliclazide in normal and analbuminemic rats.

The hypoglycemic action and disposition of gliclazide, an oral antidiabetic drug, was investigated in normal and analbuminemic rats. Orally administered gliclazide exhibited a stronger hypoglycemic action in analbuminemic rats than in normal rats. However, the plasma concentration of the drug in the mutant was much lower than that in the normal. This apparent discrepancy may be clarified by measuring the plasma concentration of unbound gliclazide. Analbuminemic rats gave larger values for the total body clearance and steady state volume of distribution of gliclazide than normal rats. The biliary and urinary excretion rates of radioactivity after intravenous bolus administration of [3H]-gliclazide were much greater in the mutant than in the normal. The binding of gliclazide to serum in analbuminemic rats was much lower than that in normal rats. Furthermore, the radioactivities of some tissues after oral administration of [3H]-gliclazide were found to be significantly higher in the mutant than in the normal. These results clearly indicate that albumin plays an important role in the hypoglycemic activity and disposition of gliclazide in rats.

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PubMedDate not supplied

Protein-mediated hepatic uptake of rose bengal in analbuminemic mutant rats (NAR). Albumin is not indispensable to the protein-mediated transport of rose bengal.

Recent kinetic studies using in situ perfused rat liver suggested that the hepatic uptake of extensively albumin-bound ligands is mediated primarily by direct interaction of the albumin-ligand complex with the hepatocyte surface rather than by the small unbound fraction of ligand, as has been generally believed [Ockner et al., Am. J. Physiol. 245, G13 (1983)]. In order to investigate this mechanism in vivo, rose bengal (RB) was injected iv to the normal and Nagase analbuminemic mutant rats (NAR) and both the pharmacokinetic parameters and the serum protein binding parameters for the two groups were compared. The serum disappearance curves of RB in normal rats and NAR were almost superimposed, and no significant difference in various pharmacokinetic parameters including the hepatic uptake clearance (k12V1) was observed between the two groups. Nevertheless, the unbound fractions of RB in serum were approximately 4-fold (equilibrium dialysis method) and 10-fold (spectrophotometric method) higher than those in normal rats. However, in both groups of rats RB is extensively bound to plasma proteins and more than 99.8% of RB in the plasma exists as the protein-bound form. The intrinsic ability of the two groups of rats to take up unbound RB was compared using isolated liver cells. No significant difference between the two groups was observed in the initial velocity of uptake. From these findings, we concluded that the hepatic uptake of RB is primarily driven by the serum protein-bound form and not by the unbound form and that the serum protein-mediated uptake mechanism of RB was not specific only for serum albumin but also for other serum proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

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