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

• Published in: Clinical pharmacology and therapeutics Vol. 68; no. 4; p. 356
• Main Authors: McCune, J S, Hawke, R L, LeCluyse, E L, Gillenwater, H H, Hamilton, G, Ritchie, J, Lindley, C
• Format: Journal Article
• Language: English
• Published: United States 01.10.2000
• Subjects: Administration, Oral; Adult; Anti-Inflammatory Agents - pharmacology; Breath Tests - methods; Cells, Cultured; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - biosynthesis; Dexamethasone - administration & dosage; Dexamethasone - blood; Dexamethasone - pharmacology; Dextromethorphan - analogs & derivatives; Dextromethorphan - urine; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Induction - drug effects; Erythromycin - analysis; Female; Glucocorticoids - administration & dosage; Glucocorticoids - blood; Glucocorticoids - pharmacology; Hepatocytes - drug effects; Hepatocytes - enzymology; Humans; Hydroxylation - drug effects; In Vitro Techniques; Male; Mixed Function Oxygenases - biosynthesis; Predictive Value of Tests; Reference Values; Testosterone - metabolism
• ISSN: 0009-9236
• DOI: 10.1067/mcp.2000.110215

The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures. 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-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone. 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 dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59). These data demonstrate that dexamethasone at doses used clinically 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 cultures.