Pharmacokinetics of 2-butanol and its metabolites in the rat

Abstract

A pharmacokinetic model is presented to describe the biotransformation of 2-butanol (2-OL) and its metabolites (2-butanone, 3-hydroxy-2-butanone, and 2,3-butanediol) using in vivo experimental blood concentrations. A flow limited model is developed to simulate 2-OL, 2-butanone (2-ONE), 3-hydroxy-2-butanone (3H-2B), and 2,3-butanediol (2,3-BD) blood concentrations in rats after oral administration of 2-OL. Assuming the only important site of 2-OL biotransformation is the liver, the tissues included are the liver and a volume of distribution, essentially body water in the case of 2-OL and its metabolites. A distribution coefficient is found to be necessary to describe the low concentration of 3H-2B in blood after administration of 2-OL. The need for this coefficient may be due to partitioning, binding, or altered transport rates from the liver. Inhibition of 2-ONE metabolism to 3H-2B by 2-OL has been included to explain a time delay in the appearance of 3H-2B after administration of 2-OL. Subsequent experimental verification confirms the mixed function oxidase inhibitory properties of 2-OL. The model is able to simulate blood concentrations and elimination of all four compounds after the oral administration of 2-OL. Additionally, the model also simulates the results obtained after i.v. administration of 3H-2B and 2,3-BD.