title: Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics.
abstract: BACKGROUND
  In vitro findings have indicated that the novel anxiolytic drug, deramciclane, is an inhibitor of the cytochrome P(450) (CYP) 2D6 enzyme and co-administration of deramciclane and the CYP2D6 probe drug desipramine is possible in clinical practice.
  
  
  OBJECTIVE
  To evaluate the effects of deramciclane on CYP2D6 activity as measured by desipramine pharmacokinetics and pharmacodynamics using paroxetine as a positive control for CYP2D6 inhibition.
  
  
  METHODS
  Fifteen healthy subjects received either 60 mg deramciclane, 20 mg paroxetine or matched placebo for 8 days in randomized order in this double-blind, cross-over study. On day 8 of each study phase, the subjects received a 100-mg single dose of desipramine. Desipramine and its CYP2D6-dependent metabolite, 2-OH-desipramine, concentrations were measured for 240 h. Measurement of secretion of saliva, Visual Analogue Scale assessment of dryness of mouth and tiredness were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane or paroxetine co-administration with desipramine.
  
  
  RESULTS
  Repeated administration of deramciclane doubled the AUC of desipramine ( P<0.001), while paroxetine caused a 4.8-fold increase in the AUC of desipramine ( P<0.001). Significant correlations were observed with paroxetine (r(s)=0.84, P<0.001) and deramciclane (r(s)=0.51, P=0.0498) concentrations and the magnitude of increase of desipramine AUC. Both deramciclane and paroxetine decreased the formation of 2-OH-desipramine in the first-pass phase. The AUC ratio of 2-OH-desipramine/desipramine was decreased by 39% ( P<0.001) by deramciclane and by 74% ( P<0.001) by paroxetine. There were no changes in the secretion of saliva during co-administration of desipramine with deramciclane compared with placebo.
  
  
  CONCLUSIONS
  Although deramciclane seems to be a weaker inhibitor of CYP2D6 than paroxetine, dose adjustment of drugs metabolized by CYP2D6 may be needed when used concomitantly with deramciclane.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku, It. Pitkäkatu 4B, 20520 Turku, Finland. karlai@utu.fi
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Steven
authors.initials: S
authors.lastname: De Bruyn
authors.forename: Harry
authors.initials: H
authors.lastname: Björklund
authors.forename: Juha
authors.initials: J
authors.lastname: Rouru
authors.forename: Jutta
authors.initials: J
authors.lastname: Hänninen
authors.forename: Harry
authors.initials: H
authors.lastname: Scheinin
authors.forename: Markku
authors.initials: M
authors.lastname: Anttila
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001892:Camphanes / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism*; D003891:Desipramine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D014151:Anti-Anxiety Agents; D000929:Antidepressive Agents, Tricyclic; D001892:Camphanes; D019389:Cytochrome P-450 CYP2D6; C060555:deramciclane; D003891:Desipramine; C028653:2-hydroxydesipramine