Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male rats, 60 days old, were treated with chlordane during or after induction of liver cirrhosis with carbon tetrachloride to determine the effect of treatment with chlordane on the response of the rats to the disease. When liver cirrhosis was induced simultaneously with chlordane treatment the disease symptoms were aggravated; the lipid content of the tissue was lowered significantly, growth rate was significantly lower than controls and there was no apparent replacement of damaged liver tissue by liver growth. The cytochrome P450 content of the liver was similar after both treatments. Continuation of the chlordane treatment after termination of the carbon tetrachloride treatment brought about a more rapid recovery from the induced cirrhotic condition. All these responses were to a dose range one tenth the recommended "no effect" level for healthy animals.
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PMID:Effects of sub-chronic low-level dietary intake of chlordane on rats with cirrhosis of the liver. 43 63

Nilvadipine is absorbed rapidly and completely and its absolute bioavailability is about 14-19% because of its high first-pass metabolism. Maximum plasma levels and the extent of bioavailability increase proportionally with the dose. Nilvadipine is mainly excreted via the kidney as inactive metabolites. Slow tissue redistribution is probably the reason for the terminal elimination half-life of 15-20 h. There was a good correlation between the estimated tissue concentration and the reduction in blood pressure in patients. The use of the sustained-release pellet formulation can prevent plasma level peaks and thereby lessen the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine were not affected by impaired renal function, and although the bioavailability was increased in liver cirrhosis, there was no accumulation after repeated doses. There was no effect on plasma digoxin levels. The plasma concentration of nilvadipine can be affected by either activation or inhibition of the cytochrome P450 system. The use of a sustained-release once-a-day formulation to lower the peaks in plasma levels along with nilvadipine's long terminal half-life means that this well-tolerated pharmaceutical formulation can be employed in clinical trials for the treatment of hypertension and expected to work over 24 h.
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PMID:Pharmacokinetics of nilvadipine. 128 85

The modifying action of chronic liver injury on the process of hepatocarcinogenesis was investigated. To induce cirrhosis or fibrosis F344 rats received CCl4 alone or in combination with phenobarbital, either before (model 1) or after (model 2) the application of initiator, diethylnitrosamine (DENA). In these models, morphology, tumor incidence as well as polysubstrate monooxygenase system, gamma-glutamyltransferase (GGT) and glucose-6-phosphatase (G-6-Pase) were studied. The data presented show that in model 1 the tumor incidence was much lower than in rats treated with DENA alone. This reduction appeared to be associated with the decrease in cytochrome P450 content occurring in model 1 after DENA administration. Promotion of the hepatocarcinogenic process was observed when CCl4 injury followed the application of DENA (model 2). Comparison of marker enzymes in cirrhotic livers and in tumors either with or without cirrhosis indicated that changes in cytochrome P450 and G-6-Pase were rather the results of parenchymal damage, while GGT was elevated only in tumorous livers. In tumorous livers none of the xenobiotic metabolizing activities decreased as much as the cytochrome P450 content of the same samples. Thus conceivably the cytochrome P450 operates more rapidly in tumors than in normal livers.
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PMID:Modification of DENA-induced hepatocarcinogenesis by CCl4 cirrhosis. Comparison of the marker enzyme patterns. 135 Feb 34

The pharmacokinetics of diazepam in normal rats and in rats pretreated with carbon tetrachloride to induce hepatic cirrhosis (cirrhotic rats) was studied after intravenous and oral administration of the drug (4 mg/kg). Animals pretreated with this hepatotoxic agent showed a significant prolongation in the half-life of diazepam in plasma that is due more to an increase in volume of distribution rather than to a decrease in clearance. This study confirmed that diazepam was highly extracted by the rat liver and was not affected by the hepatotoxic agent, although there probably was a saturation of the activity of the cytochrome P450 enzyme when the drug was administered orally. Diazepam binds to plasma proteins to a high degree in both normal and cirrhotic rats; however, in the latter, a significant increase in the fraction of unbound drug in plasma was observed. Pretreatment of rats with carbon tetrachloride did not produce any change either in the distribution of diazepam into erythrocytes or in the disposition of the metabolite desmethyldiazepam.
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PMID:Pharmacokinetics of diazepam in the rat: influence of a carbon tetrachloride-induced hepatic injury. 140 21

The biochemistry of alcohol liver disease as it relates to clinical medicine and experimental alcohol liver disease is presented. Clinical features are emphasized in the diagnosis of alcohol liver disease, particularly as it relates to staging the disease and predictors of prognosis. Currently, it is true that the biochemical diagnosis of alcohol liver disease is at best very limited in terms of the sensitivity tests and specificity of the test. It is particularly difficult to detect alcohol liver disease biochemically in the early stages when steatohepatitis is not severe. Consequently, 50% of the patients have already developed cirrhosis at the time they are diagnosed clinically. In this review indicators of malnutrition are emphasized because they have the strongest implications regarding survival during the acute hospitalization stage of the disease. They are also the best indicators of response to therapy during the recovery phase. With respect to experimental work on the pathogenesis of alcohol liver disease, it appears that necrosis is due to the inability to increase blood flow to compensate for increased oxygen utilization. The hypothesis that mitochondrial damage is the cause of liver cell damage is regarded as less important in the pathogenesis of necrosis. The shift in the redox state during alcohol metabolism accounts for the fatty change noted in the central lobular area of the liver in animals fed alcohol. Apparently, there is strong experimental evidence that highly reactive intermediates are important in the pathogenesis of liver damage due to the induction of the isozyme cytochrome P450 IIE1 by alcohol ingestion. This mechanism is enhanced by a diet high in polyunsaturated fatty acids.
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PMID:Biochemistry of alcoholic liver disease. 141 99

The effects of ethanol and carbon tetrachloride (CCl4) upon tissue vitamin A, liver lipids, liver cytochrome P450 and hepatic morphology were investigated. It was anticipated that CCl4 treatment would have more severe effects upon vitamin A status because CCl4 provides greater hepatic injury than does ethanol. After a 2-week standardization feeding period, young male rats were divided into four groups. For 5 weeks one group of rats (n = 17) received ethanol in liquid diets (30% of calories) while another (n = 8) was exposed to CCl4 inhalation twice a week along with phenobarbital in the diet. All groups received the National Regulatory Commission recommended level for vitamin A. Comparison of ethanol and its pair-fed control group (n = 17) revealed: decreased hepatic vitamin A, no change in serum vitamin A, increased percentage of liver lipid, and cytochrome P450 with moderate fat accumulation in hepatocytes. Comparison of the CCl4-phenobarbital group with pair-fed controls (n = 8) showed: increased serum vitamin A, decreased hepatic vitamin A, increased cytochrome P450, marked hepatic fat accumulation, hepatic cell necrosis, and early cirrhosis. Thus, CCl4 (with phenobarbitol), which is a more potent hepatotoxin as evidenced by a more elevated cytochrome P450 and distorted liver morphology, not only reduced liver vitamin A, but also increased serum vitamin A. The extent of substrate and/or organ specificity remains to be elucidated.
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PMID:Effects of ethanol and carbon tetrachloride upon vitamin A status of rats. 153 Jan 40

The microsomal content and activity of the principal male-specific cytochrome P450 2C11 are reduced in cirrhotic rat liver. In order to define the pathophysiological mechanism for such changes, the present study was undertaken to determine the time course of impaired P450 2C11 expression in relation to the development of cirrhosis during intake of a choline-deficient diet. Fatty infiltration of the liver was evident after 6 weeks of intake but hepatic fibrosis was not present until 10 weeks, when fine fibrotic bands in a perisinusoidal distribution were observed. Fibrotic bands were progressively more prominent at 20 and 25 weeks and cirrhosis was established by 30 weeks of dietary intake. Portal pressure, as measured by saline manometry and indicated by splenomegaly, appeared to increase gradually after 6 weeks and by 25 weeks values were significantly greater than controls. The microsomal content of P450 2C11 and its associated steroid 16 alpha-hydroxylase activity were unchanged at 6 weeks but were decreased to around 30% of control from 10 weeks of intake of the choline-deficient diet to the end of the experimental period (30 weeks). Serum bile acids were approximately 2-fold greater in choline-deficient rats from 10 weeks. Similarly, serum estradiol concentrations were elevated (to 2.5-fold of control) in male rats after 10 weeks intake of the choline-deficient diet; this increase was sustained in 30-week cirrhotic rats. On the other hand, there was no evidence of altered serum testosterone until 30 weeks of dietary deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired expression of microsomal cytochrome P450 2C11 in choline-deficient rat liver during the development of cirrhosis. 156 Mar 81

Acetylation and N-hydroxylation of dapsone were evaluated in drug-free, non-smoking, normal subjects and subjects with cirrhosis (n = 7 for each group) after oral administration of 100 mg dapsone. Acetylation was not correlated with oral dapsone clearance or reduced in cirrhosis (0.37 +/- 0.43 versus 0.52 +/- 0.32). Fractional metabolic clearance of dapsone to its hydroxylamine was associated with dapsone oral clearance (r = 0.96, p less than 0.001, n = 14). In patients with cirrhosis, liver disease was associated with a trend to reduction in oral clearance (22%) and metabolic clearance of dapsone (48%). Protein binding was minimally reduced by cirrhosis (73% +/- 1% versus 69% +/- 3% in patients with cirrhosis (p less than 0.02). The dapsone recovery ratio was validated as a phenotypic index of the metabolic clearance of dapsone (r = 0.74, p less than 0.05). In an extended comparison of 14 patients with cirrhosis to 70 control subjects, cirrhosis was associated with reductions of 28% in dapsone recovery ratio (p less than 0.001), and 37% in acetylation ratio (p less than 0.01). Neither dapsone recovery ratio nor acetylation ratio correlated with Pugh Score, conventional liver function tests, indocyanine green clearance, or phenotypic measures of S-mephenytoin hydroxylase or debrisoquin hydroxylase activity. We conclude that cirrhosis is associated with minor changes in dapsone disposition and that dosage modification is not required. In addition, there is evidence that cirrhosis has a selective influence on activity of individual isozymes of cytochrome P450.
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PMID:The disposition of dapsone in cirrhosis. 161 7

Non-alcoholic steatohepatitis resembles alcoholic liver disease in hepatic morphology but appears to have a different natural history. We sought to assess the nature of non-alcoholic steatohepatitis by a prospective study of its clinical progression and the relationship of biochemical abnormalities to changes in serum lipids among 15 patients with this disorder. In addition, antipyrine clearance (Cl-AP), which reflects hepatic microsomal oxidative capacity, was measured serially. Although initial liver histology included micronodular cirrhosis in five cases and bridging fibrosis in another three, only one patient developed a hepatic complication during 1-10 years (median: 3.7) of follow up. This confirms the relatively benign nature of non-alcoholic steatohepatitis. Moreover, Cl-AP, which was below the normal range in 13 patients, did not change significantly during 10-40 months of follow up. However, compared with other chronic liver diseases, the reduced Cl-AP was disproportionately low relative to the uniformly normal serum albumin concentration and other indices of hepatic metabolic function. This is consistent with selective impairment of endoplasmic reticular drug oxidizing enzymes. Hyperlipidaemia was present in 11 patients. In three of these, diet-induced correction of serum triglyceride elevation was associated with reduction of hepatocellular damage as indicated by serum enzyme levels. A hypothesis that unites these and earlier findings is that release of cytokines may occur in non-alcoholic steatohepatitis and produce accumulation of free fatty acids in the liver, leading to focal necro-inflammatory lesions and the destruction or down-regulation of cytochrome P450.
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PMID:Non-alcoholic steatohepatitis: impaired antipyrine metabolism and hypertriglyceridaemia may be clues to its pathogenesis. 178 74

Absorption of felodipine is rapid and complete. A pronounced first-pass metabolism results in a bioavailability of 15%, irrespective of the oral formulation used. The peak plasma concentrations and area under the plasma concentration-time curve are linearly related to the dose. The variability in plasma concentrations is wide, and individualization of the dosage is recommended. Plasma felodipine concentrations are increased in the elderly, and in patients with congestive heart failure or liver cirrhosis; in these patients felodipine should be started at a low dosage. Food intake has no clinically significant effect on felodipine absorption. Serum digoxin concentrations are increased by felodipine in plain tablet form, but not when it is administered as extended release tablets. Activators, inducers and inhibitors of the cytochrome P450 system affect the plasma concentrations of felodipine. No displacement reactions with high affinity protein binding drugs have been observed. There is a significant correlation between plasma concentration and haemodynamic effect. The mean elimination half-life of 24h together with the extended release formulation of felodipine favours once-daily dosage in patients with hypertension.
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PMID:Felodipine clinical pharmacokinetics. 178 37


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