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흰쥐에서 사염화탄소 또는 N,N-Dimethylnitrosamine에 의한 간경화시 Theophylline의 생체내변환
박은전,김재백,손동환,고건일 한국임상약학회 1999 한국임상약학회지 Vol.9 No.1
The object of this work was to study the pharmacokinetic differences and the cause of these differences in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride treatment when aminophylline (8 mg/kg as theophylline, i.v.) was injected. The concentrations of theophylline and its major metabolite (1,3-dimethyluric acid) in plasma were determined by HPLC. In addition, formation of 1,3-dimethyluric acid from theophylline in microsomes was determined. In cirrhotic rats, the systemic clearance of theophylline was reduced to of the control value while AUC (area under the plasma concentration-time curve) and were increased to about 6 fold and 10 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to of the control value in microsomes of cirrhotic rat liver. From these results, it can be concluded that in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride the total body clearance of theophylline is markedly reduced due to a reduced hepatic metabolism.
박은전,김재백,손동환,고건일 圓光大學校 藥品硏究所 1996 藥品硏究所報 Vol.11 No.1
Hepatic cirrhosis is a common response to chronic liver injury from many causes and is one of the most common cause of all deaths. This study was carried out to develop a suitable experimental hepatic cirrhosis in rats to understand this disease and to apply for the pharmacokinetic in disease state. Following three kinds of experimental models were induced; 1)Bile duct ligation/scission (BDL/S), 2) N,N-dimethylnitrosamine(DMN), 3)Carbon tetrachloride. The hepatic cirrhosis was characterized by examining the liver/body weight ratio, serum biochemical values, hydroxyproline content in liver and histological appearance in cirrhotic rat liver(hematoxylin & eosin). The results are as follows : (1) In BDL/S, the liver was enlarged to 250% of normal liver. In contrast the liver was shrinked to 48% and 78% of the normal liver in DMN and CCI₄, respectively. (2) In CCI₄ and BDL/S, the serum ALT, AST, ALP and total bilirubin levels were significantly increased to 200-300% of normal level, while ALT and total bilirubin level were significantly increased in DMN group. (3) Hydroxyproline content in cirrhotic rat liver was significantly 200-500% higher than that of normal liver. (4) Nodular formation with fibrosis was observed in BDL/S, DMN, CCI₄ induced cirrhotic rat liver.
박은전,김재백,고건일,손동환 圓光大學校 藥品硏究所 1994 藥品硏究所報 Vol.9 No.1
This study was carried out to investigate the mechanism of altered drug elimination in hepatic diseases using theophylline as an example of a drug that is extensively metabolized by the liver and have a narrow therapeutic range. Firstly, we established the experimental hepatic cirrhosis model in rats. Three kinds of method were used to induce hepatic cirrhosis; (1) bile duct ligation/scission; (2) N, N- dimethylnitrosamine; (3) carbon tetrachloride. Secondly, the pharmacokinetics of theophyl1ine(8㎎/㎏, as theophyl1ine, i.v.) was studied in three kinds of experimental hepatic cirrhosis model. And the concentration of 1,3-dimethyluric acid (major metabolite of theophylline) in plasma of the cirrhotic rats was determined. Thirdly, the activities of the hepatic microsomal aniline hydroxylase and ethoxyresorufin-O-deethylase were determined. And as an in vitro test, theophylline metabolites were determined from the extract from the incubation mixture of the theophylline and hepatic microsomal system. The hepatic enzyme activity was correlated with the content of the metabolites formed after the incubation. The results were as follows; 1) The serum ALT, AST, ALP, total bilirubin levels and hydroxyproline content in liver of the experimental hepatic cirrhosis model were significantly elevated and the histological aspects of the liver appeared as cirrhosis. 2) In the experimental hepatic cirrhosis, the values of AUC and t_½ were significantly increased and the Cl_8 and K_10 was significantly reduced. The 1,3-dimethyluric acid was not detected in cirrhotic rats. 3) In microsomal incubation, 1,3-dimethyluric acid formation was decreased in cirrhotic rats. And the decrease in 1,3-dimethyluric acid formation in vitro was accompanied by the decline in aniline hydroxylase(P450 2E1 related) activity in experimental hepatic cirrhosis. The results indicate that in experimental hepatic cirrhosis, altered theophylline elimination is mainly due to decreased hepatic drug metabolizing activity and the biotransformation of theophylline to 1,3-dimethyluric acid may be affected by cytochrome P4502E1 .
영지로부터 추출한 다당체의 실험적 간경화에 대한 섬유화 억제효과
박은전(Eun Jeon Park),김기영(Ki Young Kim),김재백(Jae Baek Kim),김수웅(Soo Woong Kim),이승용(Seung Yong Lee),손동환(Dong Hwan Sohn) 대한약학회 1994 약학회지 Vol.38 No.3
This study was carried out to investigate the antifibrotic effects of polysaccharides extracted from Garnoderma lucidum. The biliary cirrhosis was induced by bile duct ligation/scission(BDL/S) in rats. BDL/S rats were dosed 5 mg/rat/day orally for 4 weeks after the operation. Antifibrotic effects were evaluated by serum biochemical values, serum procollagen type III peptide(PIIINP) levels, liver hydroxyproline contents, and light microscopical histology. The results obtained were as follows; 1) PIIINP levels in sera of treated BDL/S group were lowered to 50% of those of untreated BDL/S group. 2) Hydroxyproline contents in the liver of treated BDL/S group were also reduced to 83% of those of untreated BDL/S rats. 3) The hepatic damage such as hepatocellular necrosis, inflammation, bile duct proliferation and fibrosis was less severe in the livers of treated rats. These results suggest polysaccharides extracted from Garnoderma lucidum to be a promising agent for the inhibition of hepatic cirrhosis(fibrosis).
박은전(Eun Jeon Park),김재백(Jae Baek Kim),손동환(Dong Hwan Sohn),고건일(Geon Il Ko) 대한약학회 1997 약학회지 Vol.41 No.5
Hepatic cirrhosis is a common response to chronic liver injury from many causes and is one of the most common cause of all deaths. This study was carried out to compare experimental hepatic cirrhosis in rats to understand this disease and to apply for the pharmacokinetics in disease state. Following three kinds of experimental models were induced; 1) Bile duct ligation/scission (BDL/S), 2) N, N-dimethylnitrosamine(DMN), 3) Carbon tetrachloride. The hepatic cirrhosis was characterized by examing the liver/body weight ratio, serum biochemical values, hydroxyproline content in liver and histopathological lesions in cirrhotic rat liver. The results are as follows : (1) In BDL/S, the liver was enlarged to 250% of normal liver. In contrast the liver was shrinked to 48% and 78% of the normal liver in DMN and carbon tetrachloride, respectively. (2) In carbon tetrachloride and BDL/S, the serum ALT, AST, ALP and total bilirubin levels were significantly increased to 200~300% of normal level, while ALT and total bilirubin levels were significantly increased in DMN group. (3) Hydroxyproline content in cirrhotic rat liver was significantly 200~500% higher than that of normal liver. (4) Nodular formation with fibrosis was observed in BDL/S, DMN, carbon tetrachloride induced cirrhotic rat liver.