Effect of lipid solubility on hepatic first-pass metabolism of barbiturates in rabbits

Abstract

The disposition of 7 barbiturates (hexobarbital, pentobarbital, cyclobarbital, amobarbital, allobarbital, phenobarbital and barbital) followed first-order kinetics after intravenous or oral administration to rabbits. The area under the plasma concentration-time curves increased in proportion to the dose after the administration of 20–80 mg/kg of barbiturates by either route. In spite of the complete absorption of barbiturates from the gastrointestinal tract as unchanged drug, the systemic availability values after oral administration were lower than unity and decreased in proportion to the in vitro rates of metabolism of the drugs by rabbit liver microsomes. Therefore, the reduction of systemic availability of these barbiturates is considered to be a result of first-pass metabolism through the liver before reaching the systemic circulation. The hepatic intrinsic clearances of unbound drug for these barbiturates estimated from a simple perfusion model based on the clearance concept varied widely in the range of 0.18–132.94 ml/min per kg of body weight and increased with increase in the lipid solubilities. The rates of metabolism of barbiturates by microsomal enzymes have been reported to depend on the lipid solubility of the drugs. As might be expected from these relations, a good linear relationship was found between the in vivo hepatic intrinsic clearance of unbound drug and the in vitro rate of metabolism by rabbit liver microsomes. Therefore, the increased hepatic first-pass metabolism and the diminished systemic availability of orally administered barbiturates are due to the increased hepatic intrinsic clearance, which may be related to the lipid solubility, of the drugs.