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)

To delineate the factors responsible for impaired clearance in cirrhosis, we examined propranolol disposition in rats with carbon tetrachloride-induced cirrhosis and compared it with that in control animals, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. We measured the extraction ratio of propranolol by the isolated perfused liver and related it to estimates of propranolol drug-metabolizing enzyme activity in homogenates of the same livers. In control animals, drug-metabolizing enzyme activity (measured as the ratio Vmax/Km) averaged 5,319 +/- 1,193 ml/min; the extraction ratio in the perfused liver was close to 1.0 (0.97 +/- 0.01). Important decreases of microsomal enzyme activity were observed in rats treated with chlorpromazine (30 +/- 27 ml/min, p < 0.001) and in rats with acute liver injury (724 +/- 401 ml/min, p < 0.001), accounting for the decrease in the hepatic extraction ratio by the perfused liver (0.33 +/- 0.09 and 0.71 +/- 0.04, respectively, p < 0.01). In cirrhotic livers, enzyme activity was not significantly different from that of controls (3,592 +/- 1,857 ml/min) and could not account for the observed decrease in extraction (0.66 +/- 0.14, p < 0.01). The extraction of antipyrine by the isolated perfused liver was also measured as an index of microsomal enzyme activity and related to propranolol extraction. Antipyrine extraction was decreased by 90% in acute liver injury, compared with 33% in cirrhosis, suggesting a much greater reduction of microsomal enzyme activity in the former group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clearance by the liver in cirrhosis. I. Relationship between propranolol metabolism in vitro and its extraction by the perfused liver in the rat. 842 28

The metabolism of antipyrine to each of its three major metabolites 4-hydroxy-, 3-methylhydroxy- and norantipyrine has previously been demonstrated to be differentially affected in alcoholic cirrhosis. This study compared the metabolism of antipyrine to its metabolites in 30 patients with alcoholic cirrhosis to 15 patients with non-alcoholic cirrhosis and 20 healthy controls. Both groups of cirrhotic patients were comparable with respect to their disease stage, as assessed by the Child-Pugh classification. Compared to controls, patients with alcoholic and non-alcoholic cirrhosis showed a comparable significant reduction in antipyrine clearance and increase in antipyrine half-life. The reduction in antipyrine clearance was due to a reduction in the formation rate of all three antipyrine metabolites in both alcoholic and non-alcoholic cirrhotics. In both groups, the formation rate of norantipyrine was reduced to a greater extent than of 3-methylhydroxy- and 4-hydroxyantipyrine. No significant differences in the parameters of antipyrine elimination, however, were observed between patients with alcoholic and non-alcoholic cirrhosis. Parameters of antipyrine elimination correlated significantly to the Child-Pugh score and single laboratory parameters, however, the correlation coefficients were generally low (< 0.56). The present results suggest that the P450 enzymes involved in antipyrine metabolism are differentially affected in cirrhosis, but there appear to be no differences in the activity of the enzymes between alcoholic and non-alcoholic cirrhosis. Antipyrine metabolism, therefore, depends on the severity rather than the etiology of liver disease and may serve as a measure of hepatic function irrespective of the cause of liver disease.
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PMID:Antipyrine elimination in patients with alcoholic and non-alcoholic cirrhosis. 844 50

Antipyrine metabolism is widely used as an index of the drug-metabolizing reserve of the liver. It is well known that metabolism of this drug is impaired in subjects with acute hepatitis or cirrhosis, but conflicting data have been reported regarding patients with chronic postinfectious hepatitis or liver cancer. We studied conventional liver-function parameters and antipyrine metabolism (antipyrine per o.s. 18 mg/kg) in 518 subjects. One hundred and one patients had liver metastases (various primaries). Based on the number and size of lesions, the hepatic involvement was considered minimal in 47 and massive in 54 (groups B1 and B2, respectively). One hundred and two had chronic active hepatitis (CAH); 51 patients with histological evidence of fibrosis/early cirrhosis and 51 patients were without histological evidence of fibrosis/early cirrhosis. Ninety-two had histologically confirmed cirrhosis (group D), and the remaining 120 had cirrhosis and hepatocellular carcinoma (group E). The control group was composed of 103 subjects with healthy livers (group A). Antipyrine clearance (AP Cl) in CAH patients with fibrosis (0.246 +/- 0.98 mL/min per kg) was similar to that observed in patients with cirrhosis (0.223 +/- 0.148 mL/min per kg), and both values were significantly lower than that found in CAH patients without fibrosis (0.406 +/- 0.159 mL/min per kg, P < 0.01). Antipyrine clearance in patients with liver metastases (0.426 +/- 0.174 mL/min per kg) was similar to that of the healthy group (0.489 +/- 0.210 mL/min per kg). Cirrhotics and cirrhotics with hepatocellular carcinoma (HCC) presented similar degrees of impairment. Antipyrine clearance was positively correlated with serum albumin (r2 = 0.10, P = 0.01) and prothrombin time (r2 = 0.129, P < 0.01) in all groups, except those with liver metastases. In patients with CAH, the presence of fibrosis/cirrhosis is associated with impaired antipyrine metabolism. The lack of impairment in groups with liver metastases suggests that the functional hepatic reserve is maintained even in the presence of massive neoplastic invasion.
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PMID:Antipyrine clearance in chronic and neoplastic liver diseases: a study of 518 patients. 964 40

Liver transplant recipients administered gelatin (GEL) rather than human albumin solution (HAS) can become profoundly hypoalbuminemic in the early postoperative period and often have hepatic dysfunction at this time. The combined effect of these two abnormalities could be an increase in the unbound (active) concentration of low-extraction highly albumin-bound drugs, such as tacrolimus (TAC). This may increase the efficacy and/or toxicity of such drugs. We prospectively compared the clinical outcome of 69 de novo liver transplant recipients randomized primarily to TAC or cyclosporine (CYA) and secondarily to HAS or GEL therapy during the first 14 days after liver transplantation. Antipyrine clearance on the 7th postoperative day was used as a measure of liver metabolic function. Serum albumin levels were significantly lower in both GEL arms than HAS arms during the first 14 days (P <.001). Although antipyrine clearance was similar in all four trial arms, it was intermediate between that found in historic healthy controls and patients with cirrhosis (P <.0001). Serum creatinine concentrations were significantly greater in the TAC plus GEL arm than the other three arms (P <.001). The linearized treated acute rejection rate was significantly greater in the TAC plus HAS arm than the other three arms (relative risk, 2.02; 95% confidence interval, 1.07 to 3.78; P =.03). These data indicate that excess nephrotoxicity can occur with TAC in liver transplant recipients with impaired hepatic metabolism who are administered GEL. In addition, supplementary albumin may reduce the efficacy of TAC in liver transplant recipients at a time when the risk for rejection is greatest.
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PMID:Influence of albumin supplementation on tacrolimus and cyclosporine therapy early after liver transplantation. 1191 May 67


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