Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets.
BACKGROUND
CYP2D6 gene duplication causing ultrafast metabolism is one reason for failure in responding to CYP2D6-metabolized antidepressants. We studied the effect of the CYP2D6 duplication genotype on doxepin pharmacokinetics and platelet serotonin uptake and concentrations.


METHODS
Pharmacokinetics of trans (E)- and cis (Z)-doxepin and N-desmethyldoxepin were analyzed after a single dose of 75 mg doxepin in 11 ultrafast metabolizers (UM), 11 extensive metabolizers (EM) and 3 poor metabolizers (PM), identified by genotyping for CYP2D6 alleles *2, *3, *4, *5, *6, *9, *10, *35, *41 and specific analyses to characterize gene duplication. Platelet serotonin concentrations were measured by HPLC.


RESULTS
A trend for lower AUC of the active principle (sum of doxepin and N-desmethyldoxepin) in UMs versus EMs was detected (575 versus 1,000 nmol h/l, P=0.07), mainly due to the differences in desmethyldoxepin concentrations (P=0.003). Stereoselective analysis showed a significant effect of the UM genotype on (E)-doxepin pharmacokinetic parameters whereas those of (Z)-doxepin did not differ between the CYP2D6 genotype groups. The 75-mg doxepin dose had no effect on platelet serotonin concentration and uptake, but serotonin concentrations in platelets were significantly higher in UM in comparison to the EM and PM groups. At baseline, these concentrations were 462, 399, and 292 ng/10 platelets in UM, EM and PM (P<0.0001 for trend).


CONCLUSIONS
At the same dose, internal exposure to doxepin differed by more than ten-fold between the CYP2D6 genotype groups. CYP2D6 may have an effect on platelet serotonin explained by salvage pathways of 5-methoxytryptamine to serotonin mediated by CYP2D6; however, this finding requires further confirmatory experiments.
Kirchheiner
Julia
J
Institute of Clinical Pharmacology, Laboratory of Clinical Neurobiology, Charité University Medicine, Berlin, Germany. julia.kirchheiner@uk-koeln.de
Henckel
Hanns-Benjamin
HB
Franke
Leonora
L
Meineke
Ingolf
I
Tzvetkov
Mladen
M
Uebelhack
Ralf
R
Roots
Ivar
I
Brockmöller
Jürgen
J
D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics* / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004316:Doxepin / Q000493:pharmacokinetics* / Q000494:pharmacology; D020440:Gene Duplication; D005838:Genotype; D006801:Humans; D008297:Male; D012016:Reference Values; D012701:Serotonin / Q000097:blood*
D000929:Antidepressive Agents, Tricyclic; D004316:Doxepin; D012701:Serotonin; D019389:Cytochrome P-450 CYP2D6