title: CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6.
abstract: OBJECTIVE
  To assess the correlation between plasma concentrations of four commonly administered selective serotonin reuptake inhibitors (SSRIs) and the magnitude of cytochrome P450 (CYP) 2D6 inhibition.
  
  
  METHODS
  Prospective analysis.
  
  
  METHODS
  University-affiliated research laboratory.
  
  
  METHODS
  Thirty-two healthy, drug-free volunteers.
  
  
  METHODS
  Subjects were randomized to four groups and received daily administration of either fluoxetine 60 mg (as a loading dose), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg for 8 days.
  
  
  RESULTS
  The urinary concentration ratio of dextromethorphan:dextrorphan (interpreted as an in vivo index of CYP2D6 activity) was determined for each subject before and after the 8 days of receiving SSRIs. Plasma SSRI trough concentrations were measured on days 6-9. The CYP2D6 genotype was determined in a subject with an undetectable paroxetine concentration. Inhibition of CYP2D6 correlated significantly with plasma concentrations of paroxetine and fluoxetine. In contrast, no significant correlations emerged between CYP2D6 inhibition and plasma concentrations of sertraline or fluvoxamine. The subject with an undetectable paroxetine concentration was found to carry at least three functional CYP2D6 genes.
  
  
  CONCLUSIONS
  For paroxetine and fluoxetine, plasma concentrations and dosage strongly influence the magnitude of enzyme inhibition. The potential of paroxetine (a CYP2D6 substrate) as an inhibitor may be affected by the genotypes and metabolic capacities of individual subjects.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, 78284-6220, USA. lamf@uthscsa.edu
authors.forename: Y W Francis
authors.initials: YW
authors.lastname: Lam
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: Larry
authors.initials: L
authors.lastname: Ereshefsky
authors.forename: Cara L
authors.initials: CL
authors.lastname: Alfaro
authors.forename: Joe
authors.initials: J
authors.lastname: Simpson
mesh_terms: D016861:Cyclooxygenase Inhibitors / Q000097:blood* / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000378:metabolism; D003917:Dextrorphan / Q000378:metabolism; D005473:Fluoxetine / Q000097:blood / Q000494:pharmacology; D016666:Fluvoxamine / Q000097:blood / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D017374:Paroxetine / Q000097:blood / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood* / Q000494:pharmacology*; D020280:Sertraline / Q000097:blood / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan; D003917:Dextrorphan; D005473:Fluoxetine; D016666:Fluvoxamine; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline