title: Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone.
abstract: OBJECTIVE
  Cytochrome P450 (CYP) 3A4 is the main CYP isozyme involved in methadone metabolism. We investigated the influence of grapefruit juice, which contains inhibitors of intestinal CYP3A, on the steady-state pharmacokinetics of methadone.
  
  
  METHODS
  For 5 days, 8 patients undergoing methadone maintenance treatment received 200 mL water or grapefruit juice 30 minutes before and again together with their daily dose of methadone. Blood sampling for R-, S-, and R,S-methadone plasma determination was performed over a 24-hour period. CYP3A activity was determined by measuring the plasma 1'-hydroxymidazolam/midazolam ratio.
  
  
  RESULTS
  A decrease in the midazolam ratio was measured in all patients after grapefruit juice (mean +/- SD before grapefruit juice, 9.3 +/- 5.9; mean +/- SD after grapefruit juice, 3.9 +/- 1.2; P <.05). Grapefruit juice led to a mean 17% increase in the area under the curve extrapolated to 24 hours for both enantiomers of methadone (range, 3% to 29% [P <.005]; range, -4% to 37% [P <.05]; and range, 1% to 32% [P <.01]; for R-, S-, and R,S-methadone, respectively). A similar increase in peak level and decrease in apparent clearance were measured with grapefruit juice, whereas time to peak level, terminal half-life, and apparent volume during the terminal phase of R-, S-, and R,S-methadone were not affected by grapefruit juice. No symptom of overmedication was either detected by the clinical staff or reported by the patients.
  
  
  CONCLUSIONS
  Grapefruit juice administration is associated with a modest increase in methadone bioavailability, which is not expected to endanger patients. However, it cannot be excluded that a much stronger effect may occur in some patients, and thus grapefruit juice intake is not recommended during methadone maintenance treatment, in particular in patients initiating such a treatment.
authors.affiliation: Service of Medicine and Penitentiary Psychiatry, University Department of Adult Psychiatry, Lausanne, Switzerland.
authors.forename: Messaoud
authors.initials: M
authors.lastname: Benmebarek
authors.forename: Corinne
authors.initials: C
authors.lastname: Devaud
authors.forename: Marianne
authors.initials: M
authors.lastname: Gex-Fabry
authors.forename: Kerry
authors.initials: K
authors.lastname: Powell Golay
authors.forename: Christian
authors.initials: C
authors.lastname: Brogli
authors.forename: Pierre
authors.initials: P
authors.lastname: Baumann
authors.forename: Bruno
authors.initials: B
authors.lastname: Gravier
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001628:Beverages; D032083:Citrus paradisi; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008691:Methadone / Q000493:pharmacokinetics*; D008875:Middle Aged; D013237:Stereoisomerism
chemical_list: D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008691:Methadone