Effects of phenobarbital steady state levels on antipyrine clearance and distribution in the rat

A group of 15 rats received two intravenous bolus doses of antipyrine (15 mg/kg) separated by a 57 hour infusion (with bolus dose) of phenobarbital. Phenobarbital bolus doses and infusion rates were based on a preliminary pharmacokinetic study (7 rats) and were varied to achieve a broad range of steady state levels. Antipyrine and phenobarbital blood levels were measured by high pressure liquid chromatography. Antipyrine kinetics obeyed first order monoexponential decay, and the parameters (clearance, volume, half-life) were determined. Antipyrine clearance increased in all animals during phenobarbital infusions with a per cent increase ranging between 54.6 and 269 per cent. However, no significant correlation was found between the per cent increase in antipyrine clearance and phenobarbital concentration (r = 0.19). The volume of distribution of antipyrine increased in 14 of 15 animals with increases ranging between 7.7 and 45.8 per cent.