EFFECTS OF GLUCOCORTICOIDS ON PHARMACOKINETICS AND PHARMACODYNAMICS OF MIDAZOLAM IN RATS

We investigated the effect of dexamethasone (80 mg/kg per day for 2 da ys) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexa methasone for glucocorticoid (GC) potency) on both pharmacokinetics an d pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodyna mic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t(1/2)) and the area under the concentration-time curve of MDZ were significantly reduced by pretrea tment with dexamethasone to 58.9% and 44.7% of the control value, resp ectively, and the clearance of MDZ was significantly increased by dexa methasone. Similar changes observed by prednisolone pretreatment did n ot reach significance. The tin of the dexamethasone pretreatment group (14.4+/-0.7 min) was significantly shorter than that of the prednisol one group (20.9+/-1.5 min). The amount of CYP3A2 protein and the activ ity of erythromycin N-demethylase were significantly increased by dexa methasone and prednisolone pretreatments, but dexamethasone showed a g reater effect than prednisolone. Sleeping time was significantly short ened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that t he anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greate r by dexamethasone than by prednisolone, implying that the potency of CYP3Ainduction may differ among GCs even when GC activity is the same.