The plasma clearance of indocyanine green in rats with acute renal failure: Effect of dose and route of administration

The pharmacokinetics of various doses (1–7.5 mg/kg i.v.) of indocyanine green (ICG) have been studied in control rats and rats with glycerol-induced acute renal failure (ARF). The pharmacokinetic changes seen at a dose of 1 mg/kg, after jugular vein administration, were significant decreases in uraemic rats in the rate of entry of ICG into the liver (k₁₂) and in the rate of movement of dye from liver to plasma (k₂₁). Greater and more numerous changes in pharmacokinetic parameters were recorded in experiments conducted using 4.0 and 7.5 mg/kg ICG. The results from these experiments showed that in addition to significant decreases in k₁₂ and k₂₁ there was a significant reduction in the rate constant for transfer of dye from liver to bile (k₂₃). These changes were accompanied by a significant decrease in plasma clearance.In a separate series of experiments steps were taken to reduce the degree of uraemia produced by glycerol injection. The findings from these experiments showed no significant pharmacokinetic differences between control and mildly uraemic animals after administration of a dose of 7.5 mg/kg ICG. This suggests that the kinetic changes described above were a consequence of renal failure and not a direct hepato-toxic effect of glycerol.     

Hepatic transport of indocyanine green in rats chronically intoxicated with carbon tetrachloride

Hepatic transport of indocyanine green (ICG) and probable factors altering the disposition of ICG were examined in rats chronically intoxicated with carbon tetrachloride. Delays were shown in both plasma disappearance and biliary excretion of ICG in intoxicated rats. No significant difference was shown in the total amount of ICG bound to the plasma proteins. In the intoxicated rats, significant decreases were observed in the pharmacokinetic parameters, k₁₂, k₃₄ and V₂, calculated by a three-compartment model, while a significant increase was observed in k₂₁; V₁ was not altered. In both the control and intoxicated rats, the values of k₁₂·V₁ were significantly smaller than the hepatic plasma flow, and it was suggested that the plasma flow does not play a primary role in the hepatic uptake of ICG. No significant difference was observed in the elution profiles of the 100,000 g supernatant fraction on a Sephadex G-75 column, and ICG bound mainly to the X-fraction in both the control and intoxicated rats. About 90 per cent of the ICG administered intravenously was distributed to the 9000g precipitate fraction by 5 min in both groups of rats. It was concluded that a decrease in the permeability of the sinusoidal plasma membrane of the hepatocyte may explain the decrease of ICG uptake rate by the livers of the intoxicated rats.     

Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of liquiritigenin and its two glucuronides, M1 and M2, in rats

Objectives Liver disease and acute renal failure (ARF) are closely associated. The pharmacokinetics of liquiritigenin (LQ), a candidate therapy for inflammatory liver disease, and its metabolites M1 and M2 were evaluated in rats with ARF induced by uranyl nitrate (U‐ARF rats). Methods LQ was administered intravenously (20 mg/kg) or orally (50 mg/kg) in U‐ARF and control rats, and uridine diphosphate‐glucuronosyltransferases (UGT) activity and uridine 5′‐diphosphoglucuronic acid (UDPGA) concentrations were determined in the liver and intestine. Key findings After intravenous LQ administration, U‐ARF rats displayed significantly slower LQ renal clearance but no significant changes in the LQ area under the plasma concentration–time curve (AUC) compared with controls. This was because of similar hepatic UGT activity and UDPGA levels between two groups, which resulted in comparable non‐renal clearance, as well as the limited contribution of LQ renal clearance to total LQ clearance. However, the AUC and AUC_M/AUC_LQ ratios of M1 and M2 were significantly increased in U‐ARF rats because of decreased urinary excretion of M1 and M2. Similar results were observed following oral administration because of the comparable LQ intestinal metabolism in both groups and decreased urinary excretion of M1 and M2 in U‐ARF rats. Conclusions U‐ARF rats displayed decreased urinary excretion of LQ glucuronides, resulting in significantly greater AUC and metabolite ratios of M1 and M2 following LQ administration.     

Drug-protein conjugates—IV: The effect of acute renal failure on the disposition of [14C]captopril in the rat

The effect of acute renal failure (ARF) on the metabolism and covalent binding to plasma proteins (PP) of [¹⁴C]captopril ([¹⁴C]CP) was investigated in the Wistar rat in vivo and in vitro using human and rat plasma. In the rat, ARF was induced by parenteral administration of glycerol. Glycerol-induced ARF markedly reduced the renal excretion of [¹⁴C]CP, the major route of elimination of the drug in control rats, but did not alter the plasma clearance of [¹⁴C]CP. However, there was a significant increase in the plasma concentrations of [¹⁴C]CP mixed disulphides with glutathione, cysteine and PP. The increase in mixed disulphide formation did not result in an increase in the concentration of radioactivity in the lung, liver, kidney, spleen or bile. Thus, control rats excreted 9.64 ± 4.24% of the dose into bile in 3 hr while rats with ARF excreted 7.14 ± 2.46%. In vitro, [¹⁴C]CP reacted rapidly with human or rat plasma to form mixed disulphides with endogenous thiols and PP. With uraemic plasma, there was a significant decrease in the amount of [¹⁴C]CP covalently bound to PP from both man and the rat.     

Effect of uranyl nitrate-induced acute renal failure on the pharmacokinetics of sulfobromophthalein in rats

The effect of acute renal failure (ARF) on the pharmacokinetics of sulfobromophthalein (BSP) was investigated in order to elucidate if renal failure modifies the hepatic metabolism of drugs. ARF was induced by intravenous (iv) injection of uranyl nitrate (UN) to rats (5 mg/kg) five days before the experiment. Area under the plasma concentration-time curve (AUC) of BSP after portal vein (pv) injection increased by 2-fold and total body clearance (CL _t) decreased one half (p<0.01) in UN-induced ARF (UN-ARF) rats compared to the control rats. But the plasma disappearance of BSP afteriv injection did not differ significantly between control and UN-ARF rats. Since BSP is excretedvia the liver,CL _t representd the approximate hepatic clearance of BSP. Therefore, the decrease inCL _t represents a decrease in hepatic intrinsic clearance (CL _int) for BSP since plasma free fraction (f _p) of BSP was not affected by UN-ARF. The content of hepatic cytoplasmic Y-protein, which catalyzes BSP-glutathione conjugation and limits the transfer of BSP from blood to bile, increased significantly (p<0.01), however its binding activity (BA) for BSP was decreased significantly (p<0.01) by UN-ARF. The decrease inCL _int might have some correlation with the changed characteristics of hepatic Y-protein, specifically its decreased BA for BSP.     

Renal Excretion of Vancomycin in Rats with Acute Renal Failure

We have investigated the renal excretion of vancomycin in rats with acute renal failure (ARF) induced by uranyl nitrate or cisplatin. The renal clearance of the antibiotic after uranyl nitrate or cisplatin injection was separately evaluated by calculating the glomerular filtration rate (GFR) and secretory clearance. The reduced renal clearance of vancomycin in these ARF rats was a result of a decrease in both GFR and secretory clearance. The extents of the decreases in GFR and in secretory clearance were not, however, proportional, the extent of the decrease in secretory clearance being more pronounced. These results suggest that the renal tubular secretion of vancomycin was reduced more predominantly than glomerular filtration in these ARF models.     

Pharmacological investigations of Punica granatum in glycerol-induced acute renal failure in rats

Objective:

The present study was designed to investigate the ameliorative potential and possible mechanism of hydroalcoholic extract of flowers of P. granatum in glycerol-induced acute renal failure (ARF) in rats.

Materials and Methods:

The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 ml/kg) and the animals were sacrificed after 24 hours of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury.

Results:

Pretreatment with hydroalcoholic extract of flowers of P. granatum (125 and 250 mg/kg p.o. twice daily for 3 days) significantly attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner. BADGE (Bisphenol-A-diglycidyl ether) (30 mg/kg), a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, and N(omega)-nitro-l-arginine-methyl ester (L-NAME) (10, 20, and 40 mg/kg), nitric oxide synthase inhibitor, were employed to explore the mechanism of renoprotective effects of Punica granatum. Administration of BADGE (30 mg/kg) and L-NAME (40 mg/kg) abolished the beneficial effects of P. granatum in glycerol-induced renal dysfunction.

Conclusion:

Hydroalcoholic extract of flowers of P. granatum has ameliorative potential in attenuating myoglobinuric renal failure and its renoprotective effects involve activation of PPAR-γ and nitric oxide-dependent signaling pathway.     

Effect of chlorpromazine on hepatic transport of indocyanine green in rats

The effect of chlorpromazine hydrochloride (CPZ) on the hepatic transport of indocyanine green (ICG) was studied in the rat, in an attempt to elucidate the mechanisms of hepatotoxicity of CPZ in vivo, by comparing the pharmacokinetic parameters of ICG after bolus and chronic administration of CPZ. Delays were shown in both plasma disappearance and biliary excretion of ICG in the CPZ-treated rats (10 and 15 mg/kg intraportal bolus administration). Significant decreases were observed in the pharmacokinetic parameters, V₂ and total body clearance (CL_tot) in CPZ 10 mg/kg treated rats and k₃₄, V₂ and CL_tot in CPZ 15 mg/kg treated rats, while a significant increase was observed in k₂₁ in both CPZ-treated groups; V₁ was not altered. The apparent liver-to-plasma concentration ratio (K_p,app) of ICG at 50 min after i.v. administration was decreased significantly in CPZ 15 mg/kg treated rats when compared to control rats, suggesting an alteration in the distribution of ICG to the liver by CPZ. Bile flow rates decreased immediately after bolus intraportal administration of CPZ in both CPZ-treated groups, and they then returned progressively to the basal levels. The output of bile acids was also inhibited by CPZ in a time-dependent and reversible manner and the bile acid independent fraction of bile flow was decreased significantly in both CPZ-treated groups. Chronic treatment with CPZ (10 or 20 mg/kg, i.p., per day for 3 weeks) did not alter either the pharmacokinetic parameters or the bile secretion profile of ICG, although there were significant decreases in body and liver weights in CPZ-treated groups. This may have been due to the rapid metabolism and excretion of CPZ in the rat when compared to humans. It is proposed that the acute toxic effect of CPZ on hepatic transport of ICG in the rat may be due mainly to the time-dependent and reversible cholestasis induced by CPZ, and that chronic treatment with CPZ may not alter the hepatic transport of ICG in the rat.     

Pharmacokinetics and hepatic extraction of metoprolol in rats with glycerol-induced acute renal failure

The aim of the present study was to evaluate the effect of glycerol-induced acute renal failure (ARF) on the pharmacokinetics and hepatic extraction of metoprolol in rats. Experimental ARF in rats was induced by injections of 50% glycerol into the leg muscle (10 ml/kg). Pharmacokinetics and hepatic extraction of metoprolol was evaluated by means of intravenous, intra-intestinal, and intra-portal administration of the drug. The blood metoprolol concentration following intravenous infusion in ARF rats was similar to that in control rats. On the other hand, the blood metoprolol concentration at 5--10 min after intra-intestinal administration in ARF rats was significantly higher than that in control rats, and the oral clearance (CL/F) of the drug was significantly decreased in ARF rats. Hepatic extraction following intra-portal infusion was not altered by glycerol-induced ARF; however, hepatic first-pass extraction of metoprolol was dose-dependent and saturable in both ARF and control rats. These results suggested that the decreased CL/F of metoprolol in rats with glycerol-induced ARF is mainly a result of the increased initial absorption rate in the intestine followed by partial saturation of hepatic first-pass metabolism.     

Protective effects of FK453, a potent nonxanthine adenosine A1 receptor antagonist,on glycerol-induced acute renal failure in rats

The purpose of the present study was to examine the protective effect of FK453, (+)-(R)-1-[(E)-3-(2-phenylpyrazolo [1,5-a] pyridin-3-yl) acryloyl]-2-piperidine ethanol, a potent non-xanthine (adenosine A₁ receptor antagonist, on glycerol-induced acute renal failure (ARF) in rat in comparison with the effects of FR113452 (S-(-) enantiomer of FK453), 1,3-dipropyl-8-cyclopentyl-xanthine (adenosine A₁ receptor antagonist), theophylline (nonselective adenosine receptor antagonist), CGS15943 [1,2,4] triazolo [1,5-C] quinazolone, adenosine A_2A receptor antagonist), and typical diuretics (hydrochlorothiazide and furosemide). FK453 (1 and 10 mg/kg orally) significantly reduced serum creatinine and urea concentrations in 25% glycerol (10 ml/kg intramuscularly)-induced ARF by protective treatment. The effect was similar to that of 1,3-dipropyl-8-cyclopentyl-xanthine and theophylline. FR113452 and CGS15943 had little effect on serum creatinine and urea concentrations. In contrast, hydrochlorothiazide and furosemide increased serum creatinine and urea concentrations. FK453, hydrochlorothiazide, and furosemide did not have any effect on either serum creatinine or urea concentration in 25% glycerol-induced ARF by therapeutic treatment. In 50% glycerol (10 ml/kg im)-induced ARF, FK453 reduced serum creatinine and urea concentrations, and increased urine volume and creatinine clearance. The results of the present study showed that FK453, a potent nonxanthine adenosine A₁ receptor antagonist, ameliorated glycerol-induced ARF in the rat. The findings support the idea that adenosine is an important factor in the development of glycerol-induced ARF in the rat and that the protective effect of adenosine receptor antagonist is mediated via the adenosine A₁ receptor. Drug Dev. Res. 39:47–53 © 1997 Wiley-Liss, Inc.     

Amelioration of glycerol-induced acute renal failure in the rat with 8-phenyltheophylline: timing of intervention

The importance of timing and duration of 8-phenyltheophylline (8-PT) administration in determining its beneficial action in glycerol-induced acute renal failure (ARF) was investigated by examining the effects of a single dose of 8-PT given immediately following (0 h) glycerol injection and at 1 and 3 h after glycerol injection. 8-PT when given at 0 h significantly lowered plasma urea and creatinine concentrations and significantly increased inulin clearance when compared both to untreated animals and those that received the vehicle for the drug. By contrast, 8-PT when administered at 1 h afforded no protective effect on renal function and, when injected at 3 h, the only significant effect was lowered plasma creatinine levels when compared to untreated rats; at this latter time it did not lower plasma urea levels or improve inulin clearance. None of the 8-PT injections attenuated the increase in kidney weight associated with ARF or reduced the kidney damage as assessed by histological examination. The results show that a single administration of 8-PT made immediately following glycerol injection can ameliorate the biochemical and functional indices of impaired renal function, but does not produce an improvement in kidney morphology.     

Decreased Transport of p-Aminohippurate in Renal Basolateral Membranes Isolated from Rats with Acute Renal Failure

Transport of D-glucose, p-aminohippurate (organic anion), and tetraethylammonium (organic cation) was studied in the renal basolateral membrane vesicles isolated from rats with acute renal failure (ARF). ARF was induced by a single injection of uranyl nitrate. Carrier-mediated transport of p-aminohippurate, estimated under anion–anion exchange condition, was significantly decreased in basolateral membrane vesicles isolated from ARF rats. In contrast, there were no significant differences in D-glucose and tetraethylammonium uptake between normal and ARF rats. When normal basolateral membrane vesicles were incubated in vitro with uranyl nitrate, no significant inhibition in p-aminohippurate uptake was observed. These results suggest that organic anion transport is decreased in renal basolateral membranes from ARF rats, and this transport dysfunction cannot be explained by the direct interaction of uranyl nitrate with the organic anion carrier.     

Influence of glycerol-induced acute renal failure on the pharmacokinetics of cyclosporin in rats.

Although it is widely believed that renal dysfunction has no effect on the pharmacokinetics of cyclosporin, many clinical reports suggest that renal dysfunction after renal transplantation is closely related to the pharmacokinetics of cyclosporin. To clarify the relationship between renal dysfunction and the pharmacokinetics of cyclosporin, we examined the influence of acute renal failure (ARF) on its pharmacokinetics in glycerol-induced ARF rats. The values of indicators of renal function (serum creatinine, blood urea nitrogen), but not those of indicators of hepatic function, were significantly increased in ARF rats that received glycerol compared with values for control rats. The area under the blood cyclosporin concentration-time curve after oral administration (AUCpo) were 4.976+/-0.847 mghL(-1) for ARF rats and 9.684+/-1.100 mghL(-1) for control rats; AUCpo in ARF was significantly reduced in a manner dependent on renal function. The oral clearance of cyclosporin in ARF and control rats was 1.172+/-0.207 and 0.544+/-0.062Lh(-1) kg(-1), respectively, whereas total body clearance in ARF and control rats was 0.151+/-0.008 and 0.183+/-0.010Lh(-1)kg(-1), respectively. The relative bioavailability of cyclosporin in ARF and control rats was 0.118 and 0.336, respectively. In an in-vitro study using everted sac and liver-slice methods, the apparent first-order rate constants for cyclosporin uptake (k(uptake)) and metabolism (k(metab)) in gut tissues were reduced, whereas k(uptake) and k(metab) in liver were increased. Gastric emptying, measured by use of paracetamol, was significantly reduced in ARF rats. These results suggest that glycerol-induced ARF results in several changes in the pharmacokinetics of cyclosporin in rats. From these results, we conclude that reduction of the absorbed fraction of cyclosporin strongly contributes to the decrease in AUCpo in the presence of ARF.     

Drug binding defect of uraemic plasma: Unlikely involvement of carbamoylated albumin

Carbamoylation of bovine and human albumin _vitro decreased the binding of methyl red and salicylic acid. Charcoal extraction of the carbamoylated albumin under acid conditions produced some decrease in the degree of carbamoylation. but did not substantially improve the binding of methyl red and salicylate. Albumin from rats with glycerol-induced acute renal failure showed no significant degree of carbamoylation compared to controls. Carbamoylation is not responsible for the binding defect of uraemic rat plasma, nor is it likely to be involved in the case of human uraemic plasma.     

No effect of diltiazem on the hepatic clearance of indocyanine green in the rats

In order to investigate the effect of the pretreatment with various doses of diltiazem (DTZ) on the pharmacokinetics of indocyanine green (ICG) at steady state, especially the hepatic blood clearance due to the change of hepatic blood flow, the following experiments were carried out with ICG, a hepatic function test marker, not metabolized in liver and only excreted in bile. The intravenous bolus injection (3,780 μg/kg) and the constant-rate infusion (10, 100 μg/kg/hr) or ICG into the left femoral vein were made in order to check the steady-state plasma concentration (C _ss of 10 μg/ml) of ICG at 20, 25 and 30 min. Following a 90-min washout period, the intravenous bolus injection (108, 430, 860 and 1,720 μg/kg) and the constant-rate infusion (108, 433, 866 and 1,730 μg/kg/hr) of DTZ into the right femoral vein were made and the achievement of the steady-state plasma levels (C _ss of 50, 200, 400 and 800 ng/ml) of DTZ were conformed at 60, 70 and 80 min. During the steady state of DTZ, the intravenous bolus injection (3,780 μg/kg) and the constant-rate infusion (10,200 μg/kg/hr) of ICG into the left femoral vein were made and also the steady-state plasma concentration of ICG was checked at 20, 25 and 30 min. The plasma concentrations of DTZ and ICG were determined using a high performance liquid chromatographic technique. At the steady state, the hepatic blood clearance of ICG was obtained from the plasma concentration and blood-to-plasma concentration ratio (R _b ) of ICG. The pretreatment with various doses of DTZ did not influence the plasma concentrations,R _B and plasma free fraction (f _p ) of ICG. So the hepatic blood clearance of ICG was independent of concentration of DTZ. The hepatic blood clearance of ICG could be affected by both hepatic blood flow and hepatic intrinsic clearance. But there was no change of the hepatic blood clearance of ICG between the control and the DTZ-pretreated rats in this study. So it may be suggested that DTZ does not influence hepatic blood flow.     

Protective effect of naringin, a bioflavonoid on glycerol-induced acute renal failure in rat kidney

Rhabdomyolysis-induced myoglobinuric acute renal failure accounts for about 10-40% of all cases of acute renal failure (ARF). Reactive oxygen intermediates have been demonstrated to play an etiological role in myoglobinuric renal failure. This study was designed to investigate the effect of naringin, a bioflavonoid with antioxidant potential, in glycerol-induced ARF in rats. Five groups of rats were employed in this study, group I served as control, group II was given 50% glycerol (8 ml/kg, intramuscularly), group III, IV, and V were given glycerol plus naringin 100, 200, and 400mg/kg p.o. route, respectively) 60 min prior to the glycerol injection. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine, and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Glycerol treatment resulted in a marked renal oxidative stress and significantly deranged the renal functions. Pretreatment of animals with naringin 60 min prior to glycerol injection markedly attenuated renal dysfunction, morphological alterations, reduced elevated thiobarbituric acid reacting substances (TBARS), and restored the depleted renal antioxidant enzymes. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of naringin in glycerol-induced renal failure in rats.     

Theophylline neurotoxicity is unaffected by glycerol-induced renal failure

Glycerol acute renal failure (ARF) was examined to see if it alters theophylline (Th) neurotoxicity in rats. Concentrations of Th in serum, cerebrospinal fluid and in brain at seizure onset were similar in control and ARF rats infused with Th. Thus, glycerol ARF fails to alter Th neurotoxicity, an effect similar to that noted previously with uranyl nitrate but not with ureter ligation.     

Reduced hepatic uptake of propranolol in rats with acute renal failure

The effect of acute renal failure (ARF) on the hepatic uptake and metabolism of propranolol was investigated in relation to the hepatic clearance of the drug. ARF was induced by the subcutaneous injection of uranyl nitrate to rats. The uptake rate of propranolol in the isolated perfused liver was determined by the multiple-indicator dilution method and was found to decrease from 43.6 +/- 2.0 min-1 (mean +/- S.E.) in control to 29.4 +/- 1.7 min-1 in ARF (P less than 0.001). The recovery fraction of propranolol in effluent venous blood increased about twofold in ARF compared to control (P less than 0.05). The metabolic activity for propranolol was examined using the hepatic microsomal fraction prepared from control and ARF rats. There was no significant difference in the kinetics of oxidative metabolism of propranolol between two groups. These results suggest that the previously reported decrease in the hepatic clearance of propranolol in ARF is due to decreased hepatic uptake of the drug from the blood into the liver cells.