Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets

  title={Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets},
  author={Julia Kirchheiner and H. B. Henckel and Leonora Franke and Ingolf Meineke and Mladen Vassilev Tzvetkov and Ralf Uebelhack and Ivar Roots and J{\"u}rgen Brockm{\"o}ller},
  journal={Pharmacogenetics and Genomics},
Introduction 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… 

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication

CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM, and it might be good if physicians would know about the CYP2D 6 duplication genotype of their patients before administering codeine.

CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6–serotonin–dopamine crosstalk revisited

It is suggested that CYP2D6 genetic variation may potentially influence pharmacodynamic tissue sensitivity in the pituitary, presumably through disposition of an endogenous substrate (e.g. 5-methoxytryptamine).

Complexities of CYP2D6 gene analysis and interpretation

  • A. Gaedigk
  • Biology
    International review of psychiatry
  • 2013
A summary of the intricacies of CYP2D6 variation and genotype analysis is provided, knowledge that is invaluable for the translation of genotype into clinically useful information.

CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine

CYP2D6 seems to be an independent contributor to pituitary pharmacodynamic tissue sensitivity to perphenazine after accounting for DRD2 functional polymorphisms, which provides a basis for further studies on the endogenous substrates of CYP2D 6 and the rational selection of candidate genes for long-term consequences of antipsychotic-induced hyperprolactinemia.

Polymorphism in CYP2D6 and CYP2C19, members of the cytochrome P450 mixed‐function oxidase system, in the metabolism of psychotropic drugs

A recent meta‐analysis of genomewide data from the three studies capturing common variation for association with symptomatic improvement and remission revealed the absence of any strong genetic association and failed to replicate results of individual studies in the pooled data.

Phenotyping of Human CYP450 Enzymes by Endobiotics: Current Knowledge and Methodological Approaches

There appears to be a lack of clinical data for the majority of the endogenous compounds described in the literature or some important limitations to allow their use in clinical practice, and the use of multivariate models is a very promising approach to enhance prediction by combining several endogenous phenotyping metrics and other covariates.

CYP2D6 polymorphism: implications for antipsychotic drug response, schizophrenia and personality traits.

The CYP2D6 gene is highly polymorphic, causing absent (poor metabolizers), decreased, normal or increased enzyme activity (extensive and ultrarapid metabolizers). The genetic polymorphism of the

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants

Evidence from published literature is presented for CYP 2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants.

Implementation Consortium Guideline for CYP 2 D 6 and CYP 2 C 19 Genotypes and Dosing of Tricyclic Antidepressants

Evidence from published literature is presented for CYP 2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants.

Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function

Evidence on the effect of DME polymorphisms on brain function is summarized that adds to the well-known effects of DMCs on pharmacokinetics in explaining the range of phenotypes that are relevant to psychiatric practice.



Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers.

The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans and CYP2D6 PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses.

Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.

AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers, and the ASCOC provides substantial advantages compared with current methods of analysis.

Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences.

A solid basis is provided for prediction of CYP2D6 capacity, as required in drug research and routine drug treatment, and significant differences in enzymatic activity measured by the dextromethorphan metabolic ratio (MR) are shown.

Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study

The results suggest that the CYP2D6 gene duplication is a possible factor that influences the development of persistence in patients with mood disorders probably by ultrarapid drug metabolism.

Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin.

CYP2D6 is a major oxidative enzyme in doxepin metabolism; predominantly catalysing hydroxylation with an exclusive preference for the E-isomers and may explain the apparent enrichment of Z-N-desmethyldoxepin that is observed in vivo.

Elucidation of the genetic basis of the common 'intermediate metabolizer' phenotype for drug oxidation by CYP2D6.

The wild-type CYP2D6 *2[-1496 C] and the novel variant [-1496 G] allele co-segregated with lower and higher CYP 2D6 in-vivo function, respectively, as shown by phenotyping using sparteine as probe drug.

Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6.

It is proposed that this common inborn error in 5-MT O-demethylation to serotonin influences a range of neurophysiologic and pathophysiologic events.

Polymorphic Cytochrome P450 2D6: Humanized Mouse Model and Endogenous Substrates

Endogenous 5‐methoxyindolethylamines derived from 5‐hydroxytryptamine were identified as high‐affinity substrates of CYP2D6 that catalyzes their O‐demethylations with high enzymatic capacity and specificity, indicating a crucial step in a serotonin‐melatonin cycle.

Effects of clomipramine treatment on cerebrospinal fluid monoamine metabolites and platelet 3 H‐imipramine binding and serotonin uptake and concentration in major depressive disorder

In an open study of 12 inpatients who met the DSM‐III criteria for a major depressive episode, the effects of clomipramine on the monoamine metabolites 5‐HIAA, homovanillic acid (HVA), 4‐hydroxy‐3‐methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) and drug concentrations were measured simultaneously.