Pharmacokinetics and biliary excretion of bromosulphophthalein, [3H]-ouabain and [3H]-taurocholic acid in rats with glycerol-induced acute renal failure

The pharmacokinetics and biliary excretion of bromosulphophthalein (BSP), ouabain and taurocholic acid (TChA) have been studied in rats with glycerol-induced acute renal failure (ARF). In rats with ARF, the hepatic uptake and initial biliary excretion of BSP were decreased. In addition, the rate of BSP conjugation with glutathione by rat liver homogenates was also decreased. This latter change may contribute to the initial decrease in the biliary excretion of BSP. No change was found in the hepatic uptake and biliary excretion of ouabain, but the area under the concentration-time curve was increased and the plasma clearance (Clp) decreased in rats with ARF. This decrease in Clp was not due to reduced renal excretion. The decreased Clp of ouabain in rats with ARF may come from reduced tissue binding and a concomitant decrease in its volume of distribution (Vd). The hepatic handling of TChA appeared unaltered in ARF, but the rate constant for the terminal part of the concentration-time curve (beta) was decreased. This change probably resulted from a large increase in Vd in rats with ARF. It is concluded that the decreased uptake of BSP was not due to a non-specific disturbance of hepatocyte function in ARF because the hepatic handling of ouabain and TChA were unaltered.     

Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure.

1. The pharmacokinetics, biliary excretion and binding of dibromosulphophthalein (DBSP) to plasma proteins and hepatic cytosol proteins have been studied in male rats with glycerol-induced acute renal failure (ARF). 2. The rate constants for hepatic uptake, efflux from liver to plasma and excretion into bile were all significantly decreased in rats with ARF. Furthermore, the plasma clearance of DBSP was also reduced. 3. The initial (0-10 min) and maximum biliary excretion rates of DBSP were both diminished in animals with ARF. The maximum excretion rate occurred between 5-10 min in control rats and 10-15 min in rats with ARF. However, there was no statistically significant change in the percentage dose recovered from bile after 30 min. 4. The plasma-protein binding of DBSP was decreased in rats with ARF and this change was due to a significant reduction in the association constant for the primary binding sites. 5. The binding of DBSP to ligandin (Y protein) was reduced by about 38% in rats with ARF but no change was noted in binding to Z protein. Reduced binding to ligandin was accompanied by decreased total liver glutathione S-transferase (GST) activity and a 36% reduction in the GST activity of ligandin. 6. The results support the contention that altered hepatic handling of cholephilic dyes in rats with ARF may be due to reduced binding to ligandin.     

Choleresis and hepatic transport mechanisms

Summary The influence of the bile salts taurocholate and dehydrocholate on the hepatic transport of two quaternary ammonium compounds,d-tubocurarine (dTc) andN ⁴-acetylprocainamide ethobromide (APAEB) was investigated in rats. The biliary excretion of APAEB and dTc in vivo was not enhanced by 106 moles/h of taurocholate or dehydrocholate. Infusion of 268 moles/h dehydrocholate caused an inhibition of the plasma disappearance and hepatic transport of dTc. This inhibition, which presumably occurred at the hepatic uptake level, was also observed in isolated perfused rat liver experiments. In animals with an intact renal function, the high dose of dehydrocholate caused a decreased biliary excretion and an increased renal excretion of dTc.The observed concentration gradients, plasma/liver cytosol and bile/liver cytosol 20 min after injection of both drugs were 1.6 and 23 for APAEB and 2.2 and 190 for dTc. These concentration ratios were based on free drug concentrations; corrections were made for plasma protein binding, intracellular binding and biliary micelle binding. No substantial binding of both compounds to ligandin and Z proteins was found. From the amount in the liver 20 min after injection of both drugs 70% of APAEB and 90% of dTc was bound to cellular particles.The rate limiting step in hepatic transport of APAEB from plasma into bile was concluded to be the hepatic uptake, which may explain the lack of effect of bile salt induced choleresis on its biliary excretion.     

The effect of acute renal failure on the pharmacokinetics of indocyanine green in the rat

The pharmacokinetics of indocyanine green (ICG) have been studied in control rats and rats with acute renal failure (ARF). Three models of ARF were investigated, and these were produced in the following ways: by bilateral ureteral ligation (surgical model), or by parenteral injection of either uranyl nitrate or glycerol. In both control and uraemic rats, from all three models of ARF, the plasma disappearance of ICG was biexponential and from the plasma disappearance curves the rate constants for transfer from plasma to liver (k₁₂), liver to plasma (k₂₁); and liver to bile (k₂₃) were calculated. The initial removal of ICG from plasma was significantly slowed and k₁₂ significantly decreased in male rats with surgically or uranyl nitrate-induced ARF. The plasma clearance of ICG was not affected by surgically-induced ARF but clearance was reduced in the uranyl nitrate model. More complex changes occurred in male rats with glycerol-induced ARF as k₁₂, k₂₁, k₂₃ and plasma clearance of ICG were all significantly decreased. Female rats with glycerol-induced ARF showed significant decreases in k₁₂, and plasma clearance, but these changes were much smaller than in uraemic males.Of the three models of ARF studied the glycerol model was preferred because surgery alone had a pronounced effect upon the kinetics of ICG and wet liver weight was significantly decreased in the uranyl nitrate model. These changes complicated interpretation of the results from the surgical and uranyl nitrate models. The results from the glycerol model suggest that the hepatic uptake of ICG, and possibly its biliary excretion, were reduced in rats with ARF. In addition, liver function in female rats appears to be more resistant than that in males to the effects of glycerol-induced ARF.     

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.     

Transport rates of hepatic uptake and biliary excretion of an organic cation, acetyl procainamide ethobromide

Rates of hepatic uptake and biliary excretion, as well as the T_max, of acetyl procainamide ethobromide (APAEB), an organic cation, were estimated in rats. The relationship between hepatic uptake and dose followed saturation kinetics. From the effect of isopropamide iodide on the uptake rate of APAEB and on the binding of APAEB to liver tissues, the saturated uptake was presumed to occur by membrane transport. The excretion rate versus the liver level, however, did not follow saturation kinetics clearly up to T_max, whereas the excretory step is considered an active process. The calculated V_max tor the excretory step was far greater than the maximal uptake rate and T_max estimated by constant infusion of APAEB, indicating that the rate-determining step in the biliary excretion of APAEB is not the excretory but the uptake step which is in contrast with that observed with many organic anions.     

Nonlinear pharmacokinetics of hepatobiliary transport of rose bengal in rats after i.v. bolus administration with varying doses.

To investigate the nonlinear kinetics in the hepatobiliary transport of rose bengal (RB), the time profiles of plasma concentration and biliary excretion rate after its i.v. administration at various doses were measured in rats. The total body clearance decreased remarkably with increased dose. The hepatic uptake clearance also showed a similar dose dependency, and saturation of hepatic uptake at least partly accounts for the dose-dependent change in total body clearance. The peak biliary excretion rate approached the transport maximum (approximately 150 nmol min-1 kg-1) with increased dose. To further clarify which process in RB hepatobiliary transport has nonlinearity, we analysed thus obtained data based on a three-compartment model. The hepatic uptake and sequestration rate constants decreased remarkably with increased dose. The initial hepatic uptake rates assessed from the plasma disappearance rate during the early phase fit well to the Michaelis-Menten equation with a saturable and a nonsaturable component. The maximum uptake velocity and Michaelis constant were 4.7 mumol min-1 kg-1 and 360 microM, respectively. That hepatic uptake has a much higher capacity (about 30 fold) than biliary excretion suggests that biliary excretion can be a rate-determining process in the overall hepatobiliary transport of RB. We conclude that the saturation of both hepatic uptake and biliary excretion could be the main causes for the nonlinear pharmacokinetics of hepatobiliary transport of RB.     

Probenecid-impaired biliary excretion of acetaminophen glucuronide and sulfate in the rat.

Acetaminophen (APAP; 100 mg/kg iv) and probenecid (50 mg/kg bolus + 11.4 mg/hr/kg infusion) were administered to male Sprague-Dawley rats to examine the disposition of APAP, and its glucuronide (AG) and sulfate (AS) conjugates in plasma, bile, and urine. Probenecid significantly decreased the formation clearance of AG from 3.65 +/- 0.434 to 1.94 +/- 0.441 ml/min/kg and the renal clearance of AS from 9.32 +/- 2.26 to 3.15 +/- 1.21 ml/min/kg. The biliary excretion of AG was reduced approximately 3- to 4-fold by probenecid, from 6.54 to 1.87% of the APAP dose, and the AG biliary excretion rate was decreased 4- to 5-fold during probenecid treatment. The more extensive impairment of AG biliary excretion relative to AG formation suggests that probenecid may inhibit the hepatobiliary transport of AG. The significant reduction in the biliary excretion rate at early time points for AS suggests that probenecid may inhibit hepatic AS transport. The study results indicate that probenecid impairs AG and AS formation, AS renal secretion, and AG and AS biliary excretion.     

Pharmacokinetics and biliary excretion of rose bengal in rats with acute and chronic renal failure

The effects of glycerol-induced acute renal failure (ARF) and surgically induced chronic renal failure (CRF) on the pharmacokinetics and biliary excretion of rose bengal have been examined in the rat. Both the pharmacokinetics and biliary excretion of rose bengal were unaltered in either ARF or CRF. The latter results in CRF contrast with those of Tse et al (1976, Int. J. Nucl. Med. Biol. 3: 134-137) who reported decreased removal of the dye from blood and reduced biliary excretion. In addition, rose bengal behaves differently from bromosulphophthalein and indocyanine green whose hepatic uptake and initial biliary excretion are known to be decreased in ARF. The results suggest that rose bengal may have a hepato-biliary transport route which differs from that of bromosulphophthalein and indocyanine green, and the findings also emphasize the selective nature of altered organic anion uptake by the liver in ARF.     

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.     

A possible reduction in the renal clearance of ciprofloxacin by fenbufen in rats

The change in plasma concentration-time profile, serum protein binding and renal and biliary clearances of ciprofloxacin caused by coadministration of fenbufen has been studied in rats administered an intravenous dose of ciprofloxacin (5 mg kg-1) alone or with fenbufen (10 mg kg-1). Coadministered fenbufen significantly prolonged the plasma elimination half-life of ciprofloxacin from 40.5 to 57.6 min and tended to reduce the total body clearance of this quinolone by about 20%. The extent of ciprofloxacin binding to rat serum protein was not affected by fenbufen, nor did it affect the biliary clearance of the quinolone. However, fenbufen tended to reduce renal clearance and significantly decreased the cumulative renal excretion of the quinolone during at least the first 3 h after drug administration. These results suggest a possible reduction of ciprofloxacin clearance owing to inhibition of renal excretion by fenbufen.     

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.     

Preventive effect of flavangenol on ischemia/reperfusion-induced acute renal failure in rats

The effects of flavangenol on ischemia/reperfusion-induced acute renal failure (ARF) in rats were examined. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured. Renal function in ARF rats markedly decreased at 1 d after reperfusion. Pre-ischemic treatment with flavangenol (3-30 mg/kg, i.v.) attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damage, such as tubular necrosis and proteinaceous casts in tubuli, which were also significantly suppressed by the administration of flavangenol. These findings suggest that flavangenol supplementation may be a promising candidate for treatments to improve the ischemia/reperfusion-induced renal injury.     

The effect of altered hepatic function on the toxicity, plasma disappearance and biliary excretion of diethylstilbestrol

The present investigation was prompted by the observation that the toxicity of diethylstilbestrol (DES) was about 140 times greater in bile duct-ligated (BDL) rats than in control rats when dimethylsulfoxide was the vehicle (24-hr LD50: 0.75 vs 100 mg/kg, respectively). The DES was also more toxic (about 70 times) in the BDL rats when ethyl alcohol was the solvent (0.47 vs 34 mg/kg), and was 5 times more toxic in the BDL rats when administered in propylene glycol (100 vs 530 mg/kg). Since it appeared that altered hepatic function markedly alters the acute toxicity of DES, the plasma disappearance and biliary excretion of DES (0.118 mg/kg, iv) were measured in control rats and in rats with altered hepatic function (produced by surgical removal of two-thirds of the liver, ip injection of 1 ml CCl₄/kg, or bile duct ligation). All three procedures of altering hepatic function decreased the plasma disappearance of DES. In the BDL rats, the total plasma concentration of DES did not decrease over the 2-hr period, suggesting that even when the biliary route of excretion is blocked, other routes are not efficent for the excretion of DES. During the furst 15 min after DES administration, the biliary excretory rate of DES was 2.1 μg/min/kg in control rats and 1.2 μg/min/kg in the rats that had a $\text{2}\text{3}$ hepatectomy or CCl₄. Therefore, impaired hepatic function increased the plasma concentration and toxicity of DES as it decreased its conjugation and biliary excretion.     

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.     

Butein ameliorates renal concentrating ability in cisplatin-induced acute renal failure in rats

The present study examined whether the cisplatin-induced nephropathy could be ameliorated by administration of butein isolated from the stems of Rhus verniciflua STOCKS. The present study showed that polyuric profile was revealed in cisplatin-induced acute renal failure (ARF) rats associated with decreases in urinary sodium, potassium, chloride, and creatinine excretion, and osmolality. Among these renal functional parameters, urinary volume and osmolality were partially restored by administration of butein (10 mg/kg, i.p.), but electrolytes and creatinine excretion were not restored. Both solute-free water reabsorption and creatinine clearance were also significantly decreased in rats subjected to cisplatin. When butein was administered in rats with cisplatin-induced ARF for 4 d, solute-free water reabsorption was improved by 91% compared with that of cisplatin-induced ARF rats, but creatinine clearance was not restored. The expression levels of aquaporin 2 (AQP 2) in the inner, outer medulla, and cortex were significantly decreased in the kidney of ARF, which were partially reverted by administration of butein. In histological examination of the kidney, butein treatment partially prevented the lesions at tubules of renal cortex in cisplatin-induced ARF rats, while the lesions at glomeruli were not ameliorated. Taken together, butein ameliorates renal concentrating ability via up-regulation of renal AQP 2 water channel in rats with cisplatin-induced ARF without ameliorating effect on renal filtration defect.     

Pharmacokinetic aspects of sulfobromophthalein transport after diethyl maleate pretreatment in rats

The pharmacokinetics of sulfobromophthalein was studied in the rat after depletion of hepatic glutathione levels induced by intraperitoneal administration of diethyl maleate (4.0 mmol/kg). After an intravenous bolus injection of sulphobromophthalein (120 mumol/kg) a biexponential plasma decay was found both in control and diethyl maleate pretreated rats. The initial plasma clearance Cl12 was not modified by diethyl maleate administration. The rate constant of biliary excretion K23 was significantly lowered in diethyl maleate pretreated rats, which could by explained by the change in the biliary excretory process. The cumulative biliary excretion of sulphobromophthalein was decreased by about 50% following diethyl maleate injection, with a reduction of the percentage of conjugated dye excreted into bile.     

Effect of experimental renal failure on the pharmacokinetics of losartan in rats

The purpose of this investigation was to determine whether the pharmacokinetics of the angiotensin II receptor antagonist losartan is altered in renal failure. Male Wistar rats were pretreated with uranyl nitrate or subjected to bilateral ureteral ligation to produce acute renal failure (ARF). Saline-injected and sham-operated rats, respectively, served as controls. Uranyl nitrate-treated rats showed significantly higher serum concentrations of losartan after oral administration and the area under the serum concentration-time curve (AUC(0-24)) of losartan increased about 3-fold compared to control rats. The systemic clearance of losartan significantly decreased from 410 +/- 254ml/h/kg in control to 177 +/- 112ml/h/kg in uranyl nitrate-treated rats. In order to investigate the mechanisms of reduced clearance of losartan associated with ARF, a hepatic microsome fraction was prepared from normal and ARF rats. No significant difference was found in the metabolism of losartan by hepatic microsomes prepared from ARF and control rats. In addition, the metabolic activity of microsomes was examined in the presence of uremic rat serum. The unbound clearance of losartan and the unbound clearance associated with the formation of EXP3174 in the presence of uremic serum were significantly lower than those in the presence of control serum. Furthermore, the metabolism of losartan was inhibited by indoxyl sulfate, a uremic toxin, in an uncompetitive manner. These results suggest that ARF is associated with reduced clearance of losartan due to the inhibition of hepatic metabolism by accumulated uremic toxin(s).     

Dietary supplementation of L-carnosine prevents ischemia/reperfusion-induced renal injury in rats

The effects of dietary supplementation of L-carnosine (beta-alanyl-L-histidine) on ischemia/reperfusion-induced acute renal failure (ARF) in rats were examined. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured. Renal function in ARF rats markedly decreased at 1 d after reperfusion. Prior feeding of L-carnosine-containing diet (0.0001 w/w%) for 2 weeks attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, which were also significantly suppressed by the dietary supplementation of L-carnosine. These findings strongly suggest that L-carnosine supplementation is useful as a prophylactic treatment in the development of the ischemic ARF.