Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To provide insight into the reported reduction in the plasma clearance of diflunisal in human renal failure, this investigation evaluated several possible mechanisms for this effect in experimental renal failure. Rats with renal failure, induced by uranyl nitrate or by ureteral ligation, had both a lower plasma clearance and an increased apparent volume of distribution, a pattern resembling that seen in human renal failure. Steady-state diflunisal concentration and unbound fraction were determined in studies during a constant infusion of diflunisal to establish the relationships of concentration, protein binding and intrinsic clearance. The infusion studies revealed that the intrinsic clearance of diflunisal, i.e., the ability of enzyme system(s) to metabolize the drug, was decreased in uremia. Also, plasma protein binding of diflunisal was decreased, which may explain the increase in apparent volume of distribution in uremic rats. The decreased intrinsic clearance of diflunisal in uremic rats may be due partly to saturation of biotransformation process(es) by increasing unbound concentration as a consequence of impairment of plasma protein binding of diflunisal, and partly due to the diminished enzyme activity of glucuronidation by renal failure. The lack of an effect of the esterase inhibitor phenylmethylsulfonyl fluoride on the intrinsic clearance of diflunisal in uremic rats suggested that the reduced intrinsic clearance of diflunisal was not attributable to the systemic enzymatic hydrolysis of the ester glucuronide.
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PMID:Possible mechanisms for reduced plasma clearance of diflunisal in rat experimental renal failure. 374 71

Theophylline, the bronchodilating agent, can cause life-threatening, generalized seizures when plasma concentrations exceed the usual therapeutic concentration range. However, the plasma concentrations of theophylline associated with this neurotoxic effect vary widely between patients. To determine the reasons for the wide variation, and thereby to facilitate prevention or early treatment of theophylline-induced neurotoxicity, an animal model of theophylline-induced seizures was developed and has now been used to determine the effect of experimental renal failure on the concentrations of theophylline that cause convulsions. Adult female rats were subjected to bilateral ureteral ligation or injected with uranyl nitrate to produce renal failure or dysfunction. Sham-operated and saline-injected rats, respectively, served as controls. Theophylline was infused i.v. at either 1.03 or 2.06 mg/min until the onset of maximal seizures. Renal failure due to ureter ligation was associated with a substantial reduction of the dose of drug required to produce seizures, the concentrations of total and free (unbound) theophylline in serum and the concentrations of theophylline in the brain and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were very low and did not account for the enhanced neurotoxicity. No apparent change in the neurotoxicity of theophylline was observed in rats with uranyl nitrate-induced renal dysfunction. The results of the investigation on ureter-ligated rats are consistent with recent clinical findings of a higher incidence of theophylline-induced neurotoxicity in azotemic patients. The experimental methodology may therefore be suitable for the prospective identification of other potential clinical risk factors for theophylline neurotoxicity.
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PMID:Kinetics of drug action in disease states. XVIII. Effect of experimental renal failure on the pharmacodynamics of theophylline-induced seizures in rats. 380 13

The single dose intravenous pharmacokinetics of amiodarone (50 mg/kg) were examined in rats with 72 h of biliary stasis secondary to bile duct ligation compared with paired control animals; and in rats with uranyl nitrate induced acute renal failure compared with paired control animals. Plasma and tissue levels (liver, kidney, heart, and lung) of amiodarone (1) and its N-deethyl metabolite 2 were obtained at 4 and 24 h following drug administration. Pharmacokinetic parameters were derived from plasma samples obtained over a 24-h period. Compared with controls, biliary stasis caused a decrease in the total clearance of 1 (1.74 versus 0.35 L/h/kg) and in the volume of distribution at steady state (21.1 versus 5.0 L/kg); renal failure caused a decrease in total clearance (1.67 versus 0.9 L/h/kg) and an increase in apparent elimination half-life (13.7 versus 10.1 h). Both disease processes produced significantly higher plasma levels of 1 when compared with control animals at 4 and 24 h. However, only the cholestatic animals had consistently higher tissue levels of 1 in the face of elevated plasma levels. In normal rats, no 1 or 2 was detected in the urine after a 50 mg/kg intravenous dose of 1, and less than 0.5% of the total dose of amiodarone (1) was excreted into bile by 12 h.
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PMID:Effect of renal failure or biliary stasis on the pharmacokinetics of amiodarone in the rat. 395 23

Previous in vivo studies have shown that the presystemic clearance of p.o.-administered levo-isomer of propranolol is inhibited in rats with uranyl nitrate-induced acute renal failure. A series of steady-state single-pass rat liver perfusion studies were performed to explore the probable mechanism of the observed metabolic inhibition. When livers from normal rats were perfused with blood perfusate prepared from normal donor animals, a high extraction ratio (Eh) of 0.974 +/- 0.005 (mean +/- S.D.) was observed at an influent I-propranolol concentration of 400 ng/ml, i.e., only 2.6% of drug entering the liver escaped single-pass extraction. The extraction of I-propranolol was significantly lower (i.e., Eh = 0.906 +/- 0.017) when livers isolated from uranyl nitrate-induced renal failure rats were perfused with uremic blood; such that there was an approximate 3-fold increase in the amount of drug escaping single-pass extraction (i.e., from 2.6 to 9.4%). This difference in hepatic extraction is quantitatively consistent with the increase in p.o. systemic availability of I-propranolol observed in our previous in vivo study with the uranyl nitrate-induced renal failure rat model. When livers from normal rats were cross-perfused with uremic blood, extraction of I-propranolol was depressed to almost the same level (i.e., Eh = 0.927 +/- 0.009) as when livers from renal failure animals were perfused with uremic blood. In contrast, livers from renal failure rats cross-perfused with normal blood exhibited comparable extraction for I-propranolol (Eh = 0.970 +/- 0.010) as normal livers perfused with normal blood.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduced extraction of I-propranolol by perfused rat liver in the presence of uremic blood. 399 18

The aims of this study were to investigate the time course of carbamylation of serum proteins in animals with experimental renal failure (RF) or with high blood urea levels without RF and finally, to document the effect of these states on the binding of sulfacetamide. RF (mean serum creatinine of 24.5 mg/dL and BUN 190 mg/dL) was originated by administrating i.v. uranyl nitrate. Uremia (mean BUN of 94 mg/dL and serum creatinine of 1.3 mg/dL) was induced by giving multiple doses of urea by gavage. RF was associated with a marked increase in the carbamylation of serum proteins and in the free fraction of sulfacetamide (Sff), but the degree of carbamylation did not correlate with Sff. Uremia without RF increased the carbamylation of serum proteins and in this case, the degree of carbamylation correlated with Sff. It is concluded that in vivo, carbamylation of serum proteins modifies, in a limited manner, drug binding to serum protein.
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PMID:Carbamylation of proteins and sulfacetamide free fraction in serum in experimentally-induced high blood urea states. 408 13

Angiotensin-converting enzyme inhibitor was used in dogs with uranyl nitrate-induced acute renal failure to evaluate (1) a possible protective effect of angiotensin blockade and (2)the role of angiotensin II in the generation of renal failure in this model. Angiotensin-converting enzyme inhibitor treatment attenuated the fall in glomerular filtration rate and renal blood flow during the first 6 hours after injection of the nephrotoxic agent. A protective effect of similar magnitude was observed whether angiotensin-converting enzyme inhibitor treatment preceded, or shortly followed, the administration of uranyl nitrate. This indicates that angiotensin-converting enzyme inhibitor delivery to its intrarenal site of action remains effective after administration of the nephrotoxin. In addition, protection of glomerular filtration rate correlated with sodium and renal solute excretion. However, combined treatment with angiotensin-converting enzyme inhibitor and furosemide enhanced solute excretion but did not further improve the protection of renal function. Finally, the protective effects of angiotensin-converting enzyme inhibitor on renal function and hemodynamics were abolished by intravenous indomethacin. In conclusion, early, continuous blockade of angiotensin II protects partially against th initiation of acute renal failure. These findings support a major pathogenic role for angiotensin II in the generation phase of acute renal failure in this model. Furthermore, they suggest that an imbalance between vasoconstrictive (angiotensin II) and vasodilating factors (prostaglandins) may be operative in the early phase of uranyl nitrate-induced acute renal failure in the dog.
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PMID:Attenuation of nephrotoxic acute renal failure in the dog with angiotensin-converting enzyme inhibitor (SQ-20,881). 617 30

The effect of experimental renal failure on the intravenous and oral pharmacokinetics of l-propranolol was studied in rats. Renal failure was induced by a single intravenous injection of uranyl nitrate (5 mg/kg). Pharmacokinetic studies were carried out on the fifth day after injection of the renal toxin (renal failure group) or saline (control group). Serum concentration time course of l-propranolol was characterized after a single intravenous or oral dose as well as after five consecutive doses of the drug given at 3-hr intervals. During repetitive intravenous drug administration, steady state was reached by the second dose, i.e., within 6 hr after initiation of repetitive dosing. No significant difference in the serum concentration time course of l-propranolol was observed between control and renal failure animals. In both groups the AUC over the steady-state dosing interval was on the average 21-27% higher than the AUC after a single dose, indicating a slight decrease in the systemic clearance of l-propranolol during repetitive intravenous drug administration. An approximately two- to three-fold higher serum l-propranolol concentration was observed in renal failure animals as compared to the normal controls after both single or repetitive oral dosing. The apparent reduction in oral clearance probably reflected an inhibition of the hepatic first-pass metabolism of l-propranolol in the renal failure rat. An unexpectedly high and protracted accumulation of serum l-propranolol concentration was observed during repetitive oral drug administration. Continuing accumulation was still evident after the fifth oral dose, i.e., a period of 15 hr or approximately 10 half-lives. The mean AUC over the last dosing interval was 32.0 and 17.8 times higher than the predicted steady-state estimate based on single oral dose data for control and renal failure rats, respectively. The substantial reduction in the oral clearance during repetitive drug administration may be due to an auto-inhibition of l-propranolol metabolism.
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PMID:Pharmacokinetics of l-propranolol during repetitive dosing in normal and uranyl nitrate-induced renal failure rats. 652 Jul 44

The effect of uranyl nitrate-induced renal failure on the pharmacokinetics of the levo-isomer of propranolol in rats was investigated. The serum clearance of an i.v. dose of propranolol (1.5 mg/kg) in normal animals approached hepatic blood flow, suggesting that the systemic clearance of the drug is rate-limited by blood flow to the liver. Extensive first-pass metabolism was observed after oral administration of l-propranolol was only 7%. Renal failure had no apparent effect on the distribution and elimination of i.v. administered l-propranolol. In contrast, the area under the serum drug concentration time curve after oral administration was increased from 6.95 to 19.3 micrograms X min/ml, which corresponded to a 2.5-fold increase in the systemic availability of l-propranolol (from 7 to 18%). The gastrointestinal absorption of l-propranolol, as assessed by comparing the urinary recovery of radioactivity after i.v. and oral administration of l-[3H]propranolol, was complete in normal animals. Hence, an increase in the extent of absorption of l-propranolol in renal failure cannot be offered as a cause of increased systemic availability. Neither the in vitro nor the in vivo serum protein binding of l-propranolol differed between renal failure and control animals. The intrinsic metabolic clearance of unbound l-propranolol in renal failure rats is estimated to be about 60% lower than that in control rats. These results suggest that the previously reported increase in propranolol serum concentration after oral administration of the drug to uremic patients is due to decreased presystemic biotransformation of the drug.
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PMID:Effect of experimental renal failure on the disposition kinetics of l-propranolol in rats. 663 14

Liver cells were prepared from untreated controls, rats with various models of acute uraemia (uranyl nitrate-treated, bilaterally nephrectomised and ureter-ligated rats, rats with acute ischaemic renal failure) and sham-operated animals. Hepatocyte glucose output, pyruvate utilisation and lactate production were determined in the presence of Krebs-Ringer bicarbonate buffer with different pH values (7.1, 7.4, 7.6) using pyruvate, dihydroxyacetone, serine and fructose as substrates. In the presence of pyruvate and dihydroxyacetone a significant increase of glucose production in hepatocytes from bilaterally nephrectomised and ureter-ligated rats was observed. However, pyruvate-generated glucose production in the hepatocytes of uranyl nitrate-treated animals was unchanged, while a diminished glucose output was seen in the presence of dihydroxyacetone. A marked increase in glucose and lactate production in the presence of serine was observed in the hepatocytes of uranyl nitrate-treated, ureter-ligated and binephrectomised rats. However, lactate production from dihydroxyacetone in the liver cells of uranyl nitrate-treated animals was inhibited. In contrast to other types of uraemia, in acute ischaemic renal failure there is significantly lower hepatocyte glucose production using pyruvate as a substrate, but unchanged glucose generation from dihydroxyacetone or serine.
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PMID:The gluconeogenetic ability of hepatocytes in various types of acute uraemia. 681 Jan 92

The investigation was designed to determine the effect of experimental renal failure on the retention of free (inorganic) sulfate and on the pharmacokinetics of acetaminophen in rats. Adult male Sprague-Dawley rats with renal failure produced by uranyl nitrate treatment or ligation of ureters had much higher serum free sulfate concentrations (about 2 and 5 mM, respectively) than normal animals (about 1 mM). The time-averaged total clearance of a 100-mg/kg dose of acetaminophen was higher in animals with renal failure than in normal rats and was positively correlated with serum free sulfate concentration (r = 0.76, P less than .001). Renal failure had no effect on the total clearance of a 15-mg/kg dose of acetaminophen, apparently because free sulfate was not appreciably depleted by this small dose. A 6-hr infusion of acetaminophen, at 36 mg/kg/hr, produced steady-state plasma concentrations of about 20 micrograms/ml within 2 hr in renal failure (ureter-ligated) animals, whereas in normal animals the plasma concentrations increased continuously to about 100 micrograms/ml at 6 hr. Free sulfate concentrations in serum at the end of the infusion were about 0.2 mM in normal animals and generally greater than 1 mM in the renal failure animals. The rats with renal failure converted most of the administered dose to acetaminophen sulfate, whereas normal animals metabolized much of the drug to acetaminophen glucuronide. These observations demonstrate the important effect of the endogenous free sulfate level in the body on the elimination kinetics and metabolic fate of a drug that is subject to conjugation with sulfate.
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PMID:Effect of experimental renal failure on sulfate retention and acetaminophen pharmacokinetics in rats. 706 93


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