title: In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone.
abstract: OBJECTIVE
  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.
  
  
  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-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/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 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of North Carolina, Chapel Hill 27599-7360, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: McCune
authors.forename: R L
authors.initials: RL
authors.lastname: Hawke
authors.forename: E L
authors.initials: EL
authors.lastname: LeCluyse
authors.forename: H H
authors.initials: HH
authors.lastname: Gillenwater
authors.forename: G
authors.initials: G
authors.lastname: Hamilton
authors.forename: J
authors.initials: J
authors.lastname: Ritchie
authors.forename: C
authors.initials: C
authors.lastname: Lindley
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001944:Breath Tests / Q000379:methods; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D003915:Dextromethorphan / Q000031:analogs & derivatives* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects; D004917:Erythromycin / Q000032:analysis; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D011237:Predictive Value of Tests; D012016:Reference Values; D013739:Testosterone / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D013739:Testosterone; C028657:3-methoxymorphinan; D004917:Erythromycin; D003915:Dextromethorphan; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human