In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone

Purpose: The aims of these experiments were to determine the effect of a th erapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between de xamethasone and CYP3A4 activity in primary human hepatocyte cultures. Methods: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-depende nt testosterone 6-beta -hydroxylation was determined in human hepatocytes t reated with 2 to 250 mu mol/L dexamethasone. Results: The percent of erythromycin metabolized per hour increased from 2. 20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexa methasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .0 04). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 2 8 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (m ean decrease = 49%; P = .06). Substantial intersubject variability was obse rved in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r(2) = 0.58). In hepatocytes, dexamethasone 2 to 250 mu mol/L resulted in an average 1.7- fold to 6.9-fold increase in CYP3A4 activity respectively. The extent of CY P3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r(2) = 0.59). Conclusions: These data demonstrate that dexamethasone at doses used clinic ally increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte culture s.