title: Dynamics and persistence of CYP2D6 inhibition by paroxetine.
abstract: OBJECTIVE
  Paroxetine is both a substrate and an inhibitor of CYP2D6. The objective of the presented study was to determine the persistence of CYP2D6 inhibition after short term (6 weeks) and long term (18·7 ± 10·6 weeks) paroxetine treatment.
  
  
  METHODS
  Two the studies consisted of 30 depressive/anxiety patients each. In the first study, patients were subdivided into three groups treated with paroxetine (A1), alprazolam (A2) and paroxetine + alprazolam (A3). After 6 weeks, all the patients (A1+A2+A3) were switched to alprazolam treatment; metabolic activity was evaluated at the beginning, after 6 weeks of paroxetine/alprazolam/alprazolam + paroxetine treatment (A1/A2/A3) and 4 weeks after the switch to alprazolam treatment (Week 0, 6, 10). In the second study patients on previous long term paroxetine treatment were subdivided into two groups treated with mirtazapine (B1) or paroxetine (B2); metabolic activity of CYP2D6 was evaluated at the beginning and after 6 weeks of therapy.
  
  
  CONCLUSIONS
  Metabolic ratio of dextromethorphan to dextrorphan has normalized in all subjects after 4 weeks of paroxetine wash out in the first study. In the second study, 6 weeks after paroxetine discontinuation, restoration of metabolic activity of CYP2D6 was observed in only five of eight originally poor metabolizers.
  
  
  CONCLUSIONS
  We conclude that a wash-out period of 4 weeks seems to be sufficient for CYP2D6 disinhibition after short-term paroxetine treatment (6 weeks). On the other hand, treatment with a CYP2D6 substrate less than 6 weeks after long-term paroxetine treatment (18·7 weeks on average) could result in elevated drug plasma levels and occasionally also in drug toxicity.
authors: Department of Pharmacology, Faculty of Medicine, Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic. jurica@med.muni.cz
authors: J
authors: J
authors: Juřica
authors: A
authors: A
authors: Žourková
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000525:Alprazolam / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003863:Depression / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D003915:Dextromethorphan / Q000494:pharmacology; D003917:Dextrorphan / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003917:Dextrorphan; D017374:Paroxetine; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D000525:Alprazolam
keywords: CYP2D6; disinhibition; paroxetine