The predictive value of changes in antipyrine pharmacokinetics in halothane and paracetamol induced hepatic necrosis in rats

Hepatic damage was induced in male Fischer 344 rats by the administration of either 1% halothane (in 14% oxygen for 2 hours to phenobarbital pretreated rats) or paracetamol (750 mg/kg ip, single dose). Antipyrine pharmacokinetics were determined one day prior to and 24 hours following one of the above treatments, in order to examine the hypothesis that changes in these parameters may reflect the extent of liver damage estimated by serum ALT and pathological changes. Clearance and terminal half-life were not significantly different following halothane treatment when compared to pretreatment values (clearance 6.9 mls/min, s.e.m. = 0.46; half-life 23 mins, s.e.m. = 0.9). However, there were significant alterations (p < 0.005) in antipyrine clearance from 1.75 (s.e.m. = 0.17, n = 5) mls/min to 0.65 (s.e.m. = 0.11) mls/min and half-life, from 96 (s.e.m. = 19) to 260 (s.e.m. = 41) minutes following paracetamol treatment. There were no correlations between these parameters (post exposure) and serum alanine aminotransferase (collected at sacrifice) in either group. All animals exposed to halothane under these conditions showed hepatocyte necrosis in the region of the central veins while damage in the paracetamol treated animals was more variable. We conclude that alterations in antipyrine pharmacokinetics do not reflect the extent of liver damage following treatment with either halothane or paracetamol.