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The effect of Mdr1 induction on the pharmacokinetics of rhodamine 123 in rats.

This study was performed to evaluate the effect of dexamethasone on the intestinal, biliary and renal handling of rhodamine 123, a P-glycoprotein substrate, in rats in vivo. Initially, five groups of rats were pretreated with dexamethasone (1, 10, 25, 40, and 100 mg/kg iday a1) intrapertioneally for four days to find the most effective dexamethasone dose for P-glycoprotein induction. Western blot analyses revealed that the maximum 5.7-fold increase in the P-glycoprotein level was obtained with dexamethasone 25 mg/kg i daya1. Consequently, this dose was used to evaluate potential changes of rhodamine 123 pharmacokinetics. In dexamethasone pretreated animals, the total, biliary and renal clearances of rhodamine 123 were significantly increased (1.4-fold, 1.5-fold and 4.1-fold, respectively), together with an increase in its intestinal extraction ratio (1.8-fold). In conclusion, these results demonstrate simultaneous induction of P-glycoprotein expression and activity in the liver, kidney and intestine due to dexamethasone. P-glycoprotein is an efflux pump found in many epithelial cells with excretory function. It has been demonstrated that dexamethasone induces P-glycoprotein expression in such tissues with consequent decrease in the disposition of P-glycoprotein substrates (Marzolini et al. 2004). Therefore, we have evaluated the dose-dependency of dexamethasone pretreatment on hepatic P-glycoprotein expression in rats. Consequently, the maximum P-glycoprotein induction could be used to assess effects of dexamethasone on P-glycoprotein-mediated intestinal extraction ratio, biliary and renal clearances of rhodamine 123, a P-glycoprotein substrate, in rats in vivo.