The effect of lipopolysaccharide on the disposition of xanthines in rats

The effect of lipopolysaccharide (LPS) isolated from Klebsiella pneumoniae O3 on the pharmacokinetic behaviour and metabolism of the xanthines, theophylline and 1-methyl-3-propylxanthine (MPX), which are mainly metabolized by the liver, was investigated in rats. LPS was infused at 0.25 mg kg-1 over a period of 20-30 min, 2 h before the administration of theophylline (10 mg kg-1) or MPX (2.5 mg kg-1). Concentrations of both xanthines in plasma and concentrations of the parent drug and metabolites in urine were measured by HPLC. Model-independent methods were applied to estimate the pharmacokinetic parameters for both xanthines. No significant changes in the pharmacokinetic parameters or metabolism of theophylline were observed in rats pretreated with LPS. However, the total body clearance and volume of distribution of MPX were significantly increased by pretreatments with LPS. Significant decreases in the binding capacity and number of binding sites on the albumin molecule were observed in the presence of LPS. Changes occurring in the protein binding behaviour as a result of the introduction of LPS is a primary factor which not only increases the volume of distribution but also increases total body clearance. These results indicate that LPS has no effect on the pharmacokinetics and metabolic pathway of theophylline although it changes the disposition of MPX due to decreases in the extent of the protein binding of MPX which is highly bound to protein.