Pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4 '-dimethoxy-5,6,5 ',6 '-dimethylenedioxybiphenyl-2-carboxylic acid-2 '-carboxylate monohydrochloride in rats with CCl4-induced acute hepatic failure
Sy. Oh et al., Pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4 '-dimethoxy-5,6,5 ',6 '-dimethylenedioxybiphenyl-2-carboxylic acid-2 '-carboxylate monohydrochloride in rats with CCl4-induced acute hepatic failure, J PHARM PHA, 52(9), 2000, pp. 1099-1103
The pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4
'-dimethoxy-5,6,5', 6'-dimethylenedioxybiphenyl-2- carboxylic acid-2'-carbo
xylate monohydrochloride (DDB-S) have been investigated in rats with CCl4-i
nduced acute hepatic failure.
To study the pharmacokinetics of DDB-S, rats were divided into a control gr
oup and a CCl4-intoxicated group. DDB-S 50 mg kg(-1) was administered by in
travenous bolus injection to both groups of rats. In the CCl4-intoxicated r
ats the plasma concentrations of DDB-S were significantly higher, the area
under the plasma concentration-time curve from time zero to time infinity w
as 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)), no
nrenal (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 r
ats. This could be due to decreased hepatic cytochrome P450 activity and im
paired kidney function induced by CCl4.
To study the hepatoprotective effects of DDB-S, rats were divided into thre
e groups, control rats and CCl4-intoxicated rats with or without DDB-S pret
reatment (50 mg kg(-1) i.p.). The effects of DDB-S pretreatment on CCl4-ind
uced liver injury were considerable; the serum levels of alanine transamina
se, aspartate transaminase, and alkaline phosphatase were significantly low
er by 54.3, 44.6 and 67.2%, respectively, compared with the CCl4-intoxicate
d-only group.
In an in-vitro study, rat hepatocytes were exposed to fresh medium containi
ng 10 mM CCl4 and various concentrations of DDB-S (10 or 100 mu g 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 co
mpared with CCl4-intoxication only.
These results indicate that DDB-S has hepatoprotective activity.