Pharmacokinetic interaction of cytochrome P450 3A-related compounds with rhodamine 123, a P-glycoprotein substrate, in rats pretreated with dexamethasone.

摘要

The effect of pretreatment with dexamethasone (DEX) on drug-drug interactions between rhodamine 123 (Rho123), a P-glycoprotein (P-gp) substrate, and midazolam, a cytochrome P450 (CYP) 3A substrate, or verapamil, a P-gp/CYP3A substrate, was studied in rats. Rats were pretreated with DEX (100 mg/kg/day, oral) for 2 days. Western blot analysis with a monoclonal antibody for P-gp, C219, revealed that DEX pretreatment increased P-gp level in the intestine 1.9-fold, but not in the liver. In vitro metabolism study of erythromycin in microsomal suspensions indicated the 9.7-fold increase of CYP3A activity in the liver, but not in the intestine, by DEX pretreatment. In an in vivo study, DEX pretreatment increased P-gp-mediated exsorption clearance of Rho123 from blood to the intestinal lumen approximately 2-fold, but not biliary clearances, in good agreement with the results of Western blot analysis. In untreated rats, midazolam (100 microM) or verapamil (30 or 100 microM) added in the intestinal perfusate (single perfusion) decreased the exsorption clearance and biliary clearance of Rho123 by approximately 30 to 50%. In DEX-pretreated rats, however, the inhibitory potency of midazolam in the liver significantly decreased compared with that in untreated rats, although the potency in the intestine did not change. The inhibitory potency of verapamil decreased both in the intestine and liver by DEX pretreatment. In conclusion, it was demonstrated that DEX pretreatment affects not only P-gp-mediated disposition of Rho123 but also pharmacokinetic interactions of P-gp/CYP3A-related compounds with Rho123, probably because concentrations of substrates/inhibitors at target sites such as the intestine and liver are varied.