Impairment in the hepatic clearance of (35S)-bromosulphophthalein in paracetamol-intoxicated rats

Abstract

1 The overall functional capacity of the liver was evaluated using [35S]-bromosulphophthalein (BSP, 100 mg/kg, i.v.) in biliary fistulated adult rats pretreated orally with different doses of paracetamol (APAP) for varying time intervals. 2 The maximal hepatic damage occurred between 12-18 h after single doses of APAP (0.5 or 1 g/kg); hepatic excretory function returned to control levels by 48-72 hours. 3 Administration of either 0.5 or 1 g/kg APAP 18 h before BSP caused a dose-dependent inhibition of the choleretic effect of BSP and of the 60 min cumulative excretion of the dye, but conversely, produced a significant increase in the liver and plasma concentrations of 35S. 4 Following acute (0.25 g/kg), or subacute (0.5 g/kg, twice daily for 7 days) treatment with APAP, the total excretion of 35S in bile and the retention of 35S in the liver or plasma remained essentially the same as that for the controls. 5 In rats given single doses of 1 g/kg APAP, the hepatic uptake of the dye was significantly increased during the early stages of intoxication, while the opposite effect was observed at late periods. 6 The bile flow appeared to be inversely related to the excretion of unchanged BSP, and directly related to the excretion of the major BSP conjugate in bile. 7 The hepatic clearance of BSP was more rapid in rats treated subacutely with 0.5 or 1 g/kg APAP, than in those treated acutely with equal doses, suggesting that the intensity of APAP-induced hepatotoxicity became less severe after the repeated administration of this drug. 8 It is concluded that the hepatic uptake, metabolism and excretion of BSP are reversibly impaired following APAP-induced liver injury.