抄録
The absorption and excretion of gomisin A (TJN-101) in rats whose livers were injured by carbon tetrachloride (CCl_4) were investigated. After intravenous administration of TJN-101 at a dose of 5 mg/kg, the terminal elimination half-life was 1.5 h in the CCl_4-treated rats, which was two times that in normal rats. The mean area under the blood concentration-time curve (AUC) value of TJN-101 in the CCl_4-treated rats was twice that in normal rats, and this difference was significant (p<0.05). Therefore, the total body clearance of TJN-101 in the CCl_4-treated rats decreased less than half of that in normal rats. Similar results were observed when it was administered orally. In the CCl_4-treated rats, the serum concentration of Met. B, which was identified as a demethylenated substance and one of major metabolites, tended to decrease more than that in normal rats. On the other hand, the cumulative biliary excretion ratio of TJN-101 in 24 h after dosing in the CCl_4-treated rats was 2.5 times that in normal rats. The excretion rate of Met. B in the bile in the CCl_4-treated rats tended to be delayed. However, the quantitative variance of biliary excretion of Met. B was not found in both groups. The urinary excretion of TJN-101 or Met. B in 72 h after dosing in the CCl_4-treated rats was lower than that in normal rats. Similar results were also observed in excretion in the feces. It was speculated that these results were originated from suppression of the enzyme activity in the oxidative drug metabolism following the decrease of cytochrome P-450 induced by treatment with CCl_4 and depression of re-absorption ratio in entero-hepatic circulation by hepatic failure. Consequently, it was demonstrated that the metabolic fate of TJN-101 was more extensively different in the CCl_4-treated rats than in normal ones.
