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)

Kidney disease is generally thought to affect all segments of a nephron equally. Bricker and co-workers first proposed this as the Intact Nephron hypothesis in 1971, and evidence to date has usually supported this hypothesis. However, most supporting studies have involved severe renal failure, which may not be suitable to differentiate effects on functional sites or to test the hypothesis. The work included here examines the effects of limited renal failure on two separate functions of the nephron: glomerular filtration, as measured by inulin clearance and proximal tubular organic anion secretory function, as measured by p-aminohippuric acid (PAH) clearance. Renal failure was induced in rats by intravenous administration of uranyl nitrate, a nephrotoxin. Doses used were 0.3, 1.0, and 3.0 mg/kg rat body weight. Five days later, rats were given an intravenous infusion of PAH and inulin. Renal clearance of each compound was calculated. Results obtained in these experiments show that, at the lowest uranyl nitrate dose, PAH clearance was significantly decreased but inulin clearance was not. The ratio of CLPAH/CLIN was decreased from 2.55 in control rats to 1.21 in rats given the low dose of nephrotoxin. At higher uranyl nitrate doses, both clearance rates were significantly decreased and the ratio of CLPAH/CLIN remained close to 1.0. These results indicate that the active transport functions of the nephron can be differentiated from passive transport functions. Caution should be exercised in extrapolating renal disease changes in active renal secretion to changes in passive renal elimination and the reverse.
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PMID:Differential effects of the degree of renal damage on p-aminohippuric acid and inulin clearances in rats. 279 54

Drugs which are cleared predominantly by forming acyl-glucuronides undergo a futile cycle in which plasma drug clearance is a function of the formation, hydrolysis and renal clearance of the glucuronide conjugate. The effect of impaired renal function, induced by uranyl nitrate administration, on each component of this process was studied in rabbits using diphenylacetic acid. Uranyl nitrate administration produced a decrease in creatinine clearance of approximately 70% and diphenylacetic acid plasma clearance of approximately 35%. In healthy rabbits the primary determinant of diphenylacetic acid net clearance was the very large component of glucuronide renal clearance (14.10 ml/min/kg) compared with glucuronide formation (4.79 ml/min/kg) or glucuronide hydrolysis (2.56 ml/min/kg). Uranyl nitrate treatment reduced both creatinine clearance and the glucuronide renal clearance by approximately 70%. Renal dysfunction had little effect on the hydrolysis clearance of the glucuronide, but reduced its formation clearance by 22.8%. The reduction in plasma clearance of diphenylacetic acid was a function of both the decrease in glucuronidation (60% contribution) and the decrease in renal clearance of the glucuronide (40% contribution). This study supports the futile cycle mechanism of reversible glucuronide conjugation for acyl-glucuronides in general, and provides a mechanism for the impairment of the plasma clearance in renal failure of drugs forming acyl-glucuronides.
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PMID:Effect of renal dysfunction on the individual components of the acyl-glucuronide futile cycle. 279 62

Our previous studies using an in vivo tissue-sampling single-carotid injection method have shown that the transport of DL-propranolol into rat brain is inhibited by the serum from rats with uranyl nitrate-induced acute renal failure. The present studies were designed to examine the effect of serum from patients with renal or liver disease on the transport of DL-propranolol into the rat brain. While the binding of DL-propranolol to serum from cirrhotic patients was significantly decreased compared to normal serum, there was no change for the serum from patients with renal failure. In the carotid injection studies, the brain transport parameters such as the brain uptake index (BUI), the unidirectional extraction ratio (ET), the blood-brain barrier permeability surface area product (PSapp), and PSapp corrected for the unbound fraction (PSuapp) in rats injected with serum from patients with renal failure were significantly reduced to approximately 40-53% of those in controls. No change in BUI, ET, and PSapp was found in rats injected with serum from cirrhotic patients. However, the cirrhotic patients adopted in the present study had relatively mild liver disease (judging from the biochemical blood test), and we cannot refer to the more severe cirrhotic patients only from this study. Moreover, significant correlations were observed between the biochemical parameters (blood urea nitrogen, serum creatinine concentration) representing the degree of renal failure and the transport parameters (ET, PSapp, or PSuapp) of DL-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of serum from renal failure and cirrhotic patients on the blood-brain barrier permeability to DL-propranolol in rats. 289 49

The purpose of this investigation was to determine whether renal dysfunction is associated with an alteration in the concentration-anesthetic effect relationship of heptabarbital (HB). Adult female rats were pretreated with uranyl nitrate (5 mg/kg i.v.) to produce renal dysfunction. Saline-injected rats served as controls. The concentration-effect relationship of HB was determined both at onset of loss of righting reflex (LRR) during an i.v. infusion (0.563 mg/min) and at offset of LRR after administration of a bolus dose (82 and 111 mg/kg in renal failure and controls, respectively, inducing similar durations of effect). In renal failure HB concentrations in serum (total and free) and in brain and cerebrospinal fluid (CSF) both at onset and offset of LRR were reduced significantly. When HB was infused at different rates (0.225, 0.563 and 1.50 mg/min) rats with renal impairment had slightly increasing HB concentrations at onset of LRR with increasing infusion rate, not only in serum and brain but also in CSF. When HB was administered in different bolus doses (71, 77, 80 and 96 mg/kg i.v.) the duration of effect increased linearly with the logarithm of the dose, but HB concentrations in serum (both total and free), brain and CSF at offset of LRR were similar, indicating the absence of (inter)active metabolites. The results indicate that renal dysfunction is associated with an increased sensitivity of the brain to HB, which is unrelated to changes in the disposition of HB.
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PMID:Altered pharmacokinetic-pharmacodynamic relationship of heptabarbital in experimental renal failure in rats. 289 67

Dosage regimen adjustments because of poor renal function are often assumed to be unnecessary for extensively metabolized antidepressants. This assumption is being increasingly questioned in recognition of the role of active drug metabolites. The purpose of this study was to assess the steady-state accumulation of the new antidepressant bupropion and its three major basic metabolites in guinea pigs, with and without experimentally-induced renal failure. Two groups of guinea pigs were treated by intraperitoneal (IP) implantation of mini-osmotic pumps containing bupropion hydrochloride. Immediately after surgery, one group of animals received an injection of uranyl nitrate. After 4 days, all animals were sacrificed by decapitation following blood removal by cardiac puncture. Analysis of plasma and brain samples by high performance liquid chromatography (HPLC) for concentrations of bupropion (BUP) and its major basic metabolites, the erythro-amino alcohol (EB), the threo-amino alcohol (TB) and the hydroxy metabolite (HB) revealed greater accumulation of BUP, TB, and HB in plasma and brain of the animals with renal failure compared to controls. No difference was found between groups in the concentrations of the EB metabolite. As the guinea pig shows a BUP and metabolite plasma concentration profile similar to that seen in human studies, these results suggest that further studies of bupropion and its major metabolites are warranted in patients with impaired renal function to assess possible excessive drug and metabolite accumulation.
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PMID:The effect of experimentally-induced renal failure on accumulation of bupropion and its major basic metabolites in plasma and brain of guinea pigs. 309 70

The pharmacokinetics of phenytoin (DPH) was investigated in rats with uranyl nitrate induced renal failure, and with D-galactosamine induced hepatic failure. The serum disappearance of DPH after 10 mg/kg i.v. dose followed a two-exponential decline in normal and both types of intoxicated rats. The serum disappearance half-life (t1/2) and the volume of distribution (Vd) significantly increased in both types of intoxicated rats, while the total blood clearances (CLb) significantly decreased. The serum unbound fraction (fu) of DPH significantly increased in both types of intoxicated rats. The blood to plasma concentration ratio (RB) of DPH significantly increased in the uranyl nitrate-treated rats, while that of the D-galactosamine-treated rats did not show significant alteration. The tissue to serum concentration ratios (Kp) of most of tissues studied after i.v. bolus injection of DPH increased in both types of intoxicated rats. Except for the lung of the D-galactosamine-treated rats, the tissue to serum unbound concentration ratio (Kpu) of other tissues did not show a significant alteration. This suggested that the tissue uptake and/or binding of DPH is not affected by uranyl nitrate or D-galactosamine intoxication and that the increases in Vd and Kp are due mainly to the decrease in serum protein binding. The hepatic intrinsic clearance of unbound DPH (CLuint,H) also decreased in both types of intoxicated rats. Thus, the uranyl nitrate and D-galactosamine intoxication caused the increase in fu and the decrease in CLuint,H and these results may explain the significant decrease in CLb and increases in Vd and t1/2. The tissue concentration-time courses of DPH were predicted by a physiciologically based pharmacokinetic model and good agreement between the predicted and observed values in normal and in both types of intoxicated rats were obtained for serum, liver, kidney, brain and muscle.
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PMID:Kinetic analysis of phenytoin disposition in rats with experimental renal and hepatic diseases. 317 73

The purpose of this investigation was to determine whether the pharmacodynamics of the centrally acting skeletal muscle relaxants zoxazolamine (ZOX) and chlorzoxazone (CZX) are altered in renal failure. Male Lewis rats with renal failure due to bilateral ligation of ureters and sham-operated controls (ZOX and CZX), as well as rats with uranyl nitrate-induced renal dysfunction and saline-injected controls (ZOX only), received an infusion of ZOX or CZX until onset of loss of righting reflex. Drug concentrations in serum, brain and cerebrospinal fluid at that time were substantially lower in animals with renal failure or dysfunction than in normal controls. The ZOX concentrations in the cerebrospinal fluid correlated negatively with indices of renal function (serum creatinine and urea concentrations). Administration of a concentrated dialyzate of serum from rats with uranyl nitrate-induced renal dysfunction to normal animals also decreased the concentrations of ZOX at onset of loss of righting reflex. Thus, the sensitivity of the central nervous system of rats to the depressant action of ZOX and CZX is significantly increased by renal failure. This effect appears to be mediated, at least in part, by an endogenous, dialyzable substance that accumulates in the blood of rats with impaired renal function.
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PMID:Kinetics of drug action in disease states. XXVII. Effect of experimental renal failure on the pharmacodynamics of zoxazolamine and chlorzoxazone. 326 Jun 25

Two etiologically different models of experimental acute renal failure were induced in rats by administration of either glycerol or uranyl nitrate. Both compounds caused a substantial decrease in the glomerular filtration rate (GFR) and the net tubular secretion of tetraethylammonium bromide (TEAB) and para-aminohippuric acid (PAH). The degree of renal impairment induced by uranyl nitrate and glycerol appeared to be dose related. Deprivation of drinking water 24 hr before the administration of glycerol potentiated the renal damage. In uranyl nitrate-induced renal failure, the decline of the net tubular secretion for TEAB and PAH was not proportional to the decrease in GFR; the secretion process deteriorated faster than the GFR. For example, when 0.5 mg/kg uranyl nitrate was administered, GFR fell to approximately 65% of normal, whereas the net tubular secretion was decreased to 30% of normal. These results suggest that the tubular transport was preferentially affected by uranyl nitrate. In contrast, in glycerol-induced renal failure, the decline of TEAB secretion fell in a parallel fashion with the GFR, suggesting that the glomeruli and the proximal tubules were equally damaged by glycerol. However, in this latter model, the decline of PAH secretion did not parallel the decrease in GFR, contradicting the proposal that glycerol affects equally the glomeruli and the proximal tubules. This discrepancy may be due to the selective competitive inhibition of PAH secretion by the accumulation of naturally occurring organic acids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal handling of drugs in renal failure. I: Differential effects of uranyl nitrate- and glycerol-induced acute renal failure on renal excretion of TEAB and PAH in rats. 341 18

The binding of 2-phenylpropionic acid (2PPA) enantiomers to rabbit albumin has been studied using fatty-acid-free albumin, with and without oleic acid, and using plasma from control rabbits and from rabbits rendered uremic with uranyl nitrate. The models of binding examined included specific binding at one and at two species of binding site, nonspecific binding and with inhibition between enantiomers with competitive or noncompetitive kinetics. Although any one aspect of the data is adequately modeled by nonspecific binding together with a single species of specific site, the simplest physical model consistent with the whole data requires two species of specific site together with nonspecific binding. Oleic acid in vitro, or other modifiers in vivo, inhibit the binding at both specific sites and reduce nonspecific binding. The inhibition at one site is sufficient that the situation in whole plasma simplifies to one site plus nonspecific binding. Competition between enantiomers occurs at this remaining site, at which R-2PPA binds more avidly than S-2PPA. Both specific and non-specific binding are reduced further in uranyl nitrate-induced renal failure. In the light of these findings, we discuss the implications of enantioselective binding and of competition between enantiomers for binding sites on the interpretation of drug disposition studies.
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PMID:Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. II. 2-Phenylpropionic acid protein binding. 372 1

The pharmacokinetics of the antianginal drug isosorbide-5-nitrate (IS-5-N) was studied in 20 patients with varying degrees of chronic renal failure after repeated oral doses of standard 20 mg tablets t.d.s. Blood samples were taken in the steady state on the 2nd and 28th days, and the plasma level was assayed by HPLC. There was no statistically significant difference in Cssmax, t1/2 and AUCss0-8 between the 2nd and 28th days, nor was a difference found between patients with mild and severe renal failure.
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PMID:Pharmacokinetics of isosorbide-5-nitrate in renal failure. 373 74


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