Effect of Low and High-Dose Dexamethasone on CYP3A and P-glycoprotein Expression and Function in Mice

Dexamethasone, which acts on nuclear receptors, is used together with P-gp andCyp3a4 substrates at different doses in the treatment of diverse diseases. The aimof the study is to determine the effect of different doses of dexamethasone on the expressions and functions of P-gp and Cyp3a4 (mouse homologues of Cyp3a4 areCyp3a11 and Cyp3a13). Animals (n=54) were divided into 9 equal groups. The control group was given only water. (The second group received fexofenadine, thethird group received midazolam, the fourth group received low-dose dexamethasone,and the fifth group received high-dose dexamethasone. Low dose dexamethasonewas administered to the sixth and seventh groups, and high dose dexamethasonewas administered to the eighth and ninth groups.) 24 hours after these applications,fexofenadine was administered to the sixth and eighth groups, and midazolam was administered to the seventh and ninth groups. Synthesis of mdr1a, mdr1b, Cyp3a11and Cyp3a13 in the small intestine and liver were determined using RT-qPCR.Plasma concentrations of fexofenadine and midazolam were determined usingHPLC-UV. The effect of dexamethasone on Cyp3a11 expression was determined tobe dose-related, while its effect on P-gp expression was not dose-related. Midazolam,a CYP3A substrate, did not cause P-gp induction in the small intestine, but didcause P-gp induction in the liver. Fexofenadine and midazolam reduced the effectof dexamethasone on Cyp3a11 expression in the small intestine. Dexamethasonedose-dependently decreased the plasma concentration of midazolam and increasedthat of its metabolite. Dexamethasone caused a dose-independent decrease inplasma concentrations of fexofenadine. The effect of dexamethasone on P-gpexpression is not dose-dependent, but its effect on Cyp3a11 ve Cyp3a13 expressionis dose-dependent. Fexofenadine and midazolam caused a reduction in the effect of dexamethasone on Cyp3a11 expression in the small intestine.