Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics.
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.
Laine
Kari
K
Department of Pharmacology and Clinical Pharmacology, University of Turku, It. Pitkäkatu 4B, 20520 Turku, Finland. karlai@utu.fi
De Bruyn
Steven
S
Björklund
Harry
H
Rouru
Juha
J
Hänninen
Jutta
J
Scheinin
Harry
H
Anttila
Markku
M
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
D014151:Anti-Anxiety Agents; D000929:Antidepressive Agents, Tricyclic; D001892:Camphanes; D019389:Cytochrome P-450 CYP2D6; C060555:deramciclane; D003891:Desipramine; C028653:2-hydroxydesipramine