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KMID : 1140120050100010034
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Cancer Prevention Research
2005 Volume.10 No. 1 p.34 ~ p.47
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Effects of Hepatic Disease on Flow-limited Verapamil Pharmacokinetics in the DMN-induced Hepatic Cirrhotic Rats
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Hong Jung-Wook
Park Yun-Young
Yuan Hai-Dan
Kim Hyun-Jin
Lee Joo-Won
Jhee Ok-Hwa
Om Ae-Son
Lee Sang-Koo
Lee Yun-Sik
Shin In-Chul
Lee Min-Ho
Kang Ju-Seop
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Abstract
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The purpose of this study was to determine the effect of hepatic disease severities on pharmacokinetics of flow-limited verapamil in dimethylnitrosamine (DMN)-induced cirrhotic rats. Hepatic cirrhotic rats (SD rats, 200∼250 g) were induced by intraperitoneal injection with 1% DMN solution at a dose of 10μg/g by 3 days/week as experimental groups and same dose of saline as control for 4 weeks. The serum verapamil concentrations were quantified at zero, 10 min, 30 min, 1, 2 and 3 hrs after bolus injection of 3 mg/kg of verapamil by a column-switching HPLC method and pharmacokinetic parameters such as Co, MRT, AUC, Vdss, t1/2 (β) and CLp were determined in each group. And then some hepatic tissue was obtained and subjected to analysis of the hepatic 4-hydroxyproline content and were inspected by light microscope after hematoxylin and eosin staining. The serum concentrations and pharmacokinetic parameters such as Co, AUC, MRT and t1/2 (β) were significantly increased (p＜0.01) and Vdss and CLp were significantly decreased (p＜0.01) in hepatic cirrhotic rats according to DMN-treated period. The 4-hydroxyproline content was also gradually increased propertionally to DMN-treated period. The pharmacokinetic parameters of verapamil were seemed to change gradually to depend on the hepatic fibrotic severity. Therefore, we suggested that flow-limited drug as like verapamil dosage adjustment is necessary according to hepatic function severity. (Cancer Prev Res 10, 34-47, 2005)
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KEYWORD
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Flow-limited Verapamil, Cirrhosis, HPLC, Pharmacokinetic Parameter
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