Pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2-carboxyli c acid-2'-carboxylate monohydrochloride in rats with CCl 4-induced acute hepatic failure

Abstract

The pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2-carboxyli c acid-2'-carboxylate monohydrochloride (DDB-S) have been investigated in rats with CCl 4-induced acute hepatic failure. To study the pharmacokinetics of DDB-S, rats were divided into a control group and a CCl 4-intoxicated group. DDB-S 50 mg kg -1 was administered by intravenous bolus injection to both groups of rats. In the CCl 4-intoxicated rats the plasma concentrations of DDB-S were significantly higher, the area under the plasma concentration-time curve from time zero to time infinity was significantly greater (6.46 vs 3.34 mg min mL -1), and the total body (7.74 vs 15.0 mL min -1 kg -1), renal (2.55 vs 5.10 mL min -1 kg -1), nonrenal (5.07 vs 9.65 mL min -1 kg -1), and biliary (1.48 vs 2.69 mL min -1 kg -1) clearances were significantly slower compared with the control rats. This could be due to decreased hepatic cytochrome P450 activity and impaired kidney function induced by CCl 4. To study the hepatoprotective effects of DDB-S, rats were divided into three groups, control rats and CCl 4-intoxicated rats with or without DDB-S pretreatment (50 mg kg -1, i.p.). The effects of DDB-S pretreatment on CCl 4-induced liver injury were considerable; the serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly lower by 54.3, 44.6 and 67.2%, respectively, compared with the CCl 4-intoxicated-only group. In an in-vitro study, rat hepatocytes were exposed to fresh medium containing 10 mM CCl 4 and various concentrations of DDB-S (10 or 100 μg mL -1). The levels of alanine transaminase and aspartate transaminase in the medium were measured as an indicator of hepatocyte injury. DDB-S dose-dependently decreased the levels of alanine transaminase and aspartate transaminase compared with CCl 4-intoxication only. These results indicate that DDB-S has hepatoprotective activity.