Pharmacokinetics of fexofenadine following LPS administration to rats
The function and expression of drug transporters, including P-glycoprotein (P-gp) and organic-anion transporting polypeptides (Oatps), have been investigated but it is not well established how variables such as disease processes affect them. Fexofenadine is a substrate of these transporters and it was previously shown that its clearance is reduced in the rat isolated perfused liver following treatment with E.coli lipopolysaccharide (LPS). However, whether this translates to altered fexofenadine pharmacokinetics in vivo is yet to be established. E.coli LPS at 5?mg/kg or sterile saline (control) was injected intraperitoneally in rats. Oral or intravenous (IV) fexofenadine (10?mg/kg) was administered 24?h later and plasma and urine samples collected for pharmacokinetic analysis. LPS treatment did not significantly change the pharmacokinetics of IV fexofenadine, although there was a good correlation between weight loss and clearance suggesting reduced clearance in more severely affected animals. However, AUC0-8 of oral fexofenadine was a significantly higher in LPS-treated animals (13.9?Ό.76 min絧/ml) compared to controls (5.53?.12 min絧/ml). In conclusion, LPS treatment increased the bioavailability of fexofenadine but did not affect other pharmacokinetic parameters. This is consistent with a reduction in hepatic Oatp and/or P-gp for a high extraction ratio drug such as fexofenadine.
Pharmacology and Pharmaceutical Sciences not elsewhere classified