, Volume 17, Issue 12, pp 1511-1515

Hepatic Disposition of Fexofenadine: Influence of the Transport Inhibitors Erythromycin and Dibromosulphothalein

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Purpose. To examine the disposition of fexofenadine in the isolated perfused rat liver and the influence of erythromycin and dibromosulphthalein (DBSP) on the hepatic uptake and biliary excretion of fexofenadine.

Methods. Livers from four groups of rats were perfused in a recirculatory manner with fexofenadine HCl added as a bolus (125, 250, 500, or 1000 μg) to perfusate. Livers from another three groups of rats were perfused with 250 μg of fexofenadine HCl. With one group as control, erythromycin (4.0 μg/ml) or DBSP (136 μg/ml) was added to the perfusate of the other groups. In all experiments, perfusate and bile were collected for 60 min; in addition, livers from the second experiment were retained for assay. Fexofenadine was determined in perfusate, bile, and homogenized liver by HPLC.

Results. The area under the curve (AUC) of fexofenadine was linearly related to concentration. It was unchanged from control (12,800 ± 200 ng·h/ml) by erythromycin (14,400 ± 2000 ng·h/ml), but was increased 95% by DBSP (25,000 ± 2600 ng·h/ml, P <0.001). The ratios of the concentrations of fexofenadine in liver/perfusate were decreased significantly by DBSP; those for bile/liver were increased by erythromycin.

Conclusions. Erythromycin reduced the canalicular transport of fexofenadine into bile, whereas DBSP reduced uptake across the sinusoidal membrane.