title: The recovery time-course of CYP3A after induction by St John's wort administration.
abstract: BACKGROUND
  St John's wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St John's wort.
  
  
  CONCLUSIONS
  The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St John's wort administration
  
  
  OBJECTIVE
  To examine the recovery time course of CYP3A after enzyme induction by St John's wort administration.
  
  
  METHODS
  The subjects were 12 healthy men, aged 20-33 years. On the first day, they received an oral dose of midazolam 5 mg without St John's wort (day -14). From the next day, they took St John's wort for 14 days. On the last day of St John's wort treatment (day 0) and 3 and 7 days after completion of St John's wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis.
  
  
  RESULTS
  Apparent oral clearance of midazolam was significantly increased after St John's wort administration from 65.3 +/- 8.4 l h(-1) (day -14) to 86.8 +/- 17.3 l h(-1) (day 0). It returned to the control level 7 days after the completion of St John's wort (day 7, 59.7 +/- 3.8 l h(-1)). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St John's wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h.
  
  
  CONCLUSIONS
  CYP3A activity induced by St John's wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St John's wort with CYP3A substrates.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Imai
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kotegawa
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Takuya
authors.initials: T
authors.lastname: Morimoto
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Eshima
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nakano
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ohashi
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D018757:GABA Modulators / Q000493:pharmacokinetics*; D006801:Humans; D020902:Hypericum; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D018757:GABA Modulators; D010936:Plant Extracts; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam