The N-Demethylation of the Doxepin Isomers Is Mainly Catalyzed by the Polymorphic CYP2C19

  title={The N-Demethylation of the Doxepin Isomers Is Mainly Catalyzed by the Polymorphic CYP2C19},
  author={Sebastian H{\"a}rtter and Gunnel Tybring and Thomas H Friedberg and Harald Weigmann and Christoph Hiemke},
  journal={Pharmaceutical Research},
AbstractPurpose. This study was conducted to identify the cytochrome P450s (CYPs) responsible for the metabolism of the cis- and trans-isomers of the tricyclic antidepressant doxepin to its pharmacologically active N-desmethylmetabolite by in vitro techniques. Methods. The doxepin N-demethylation was studied by means of pooled human liver microsomes and chemical inhibitors, recombinant human (rh)-CYPs, and geno- and phenotyped human liver microsomes. Results. The N-demethylation of both isomers… 

Doxepin inhibits CYP2D6 activity in vivo.

Results show the inhibitory effect of doxepin on CYP2D6 activity and may be of clinical value, especially in polymedicated patients treated with other CYP 2D6 substrates or inhibitors.

The oxidative metabolism of dimemorfan by human cytochrome P450 enzymes.

Results indicated the participation of multiple P450 forms in DFO, and microsomal M1 and M2 formation was most sensitive to the inhibition by a CYP2D6 inhibitor, paroxetine and a CyP3A4 inhibitor, ketoconazole, respectively.

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance

There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population and the number of alleles is still growing.

Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2

Human CYP1A2 is one of the major CYPs in human liver and metabolizes a number of clinical drugs, and is induced through AhR-mediated transactivation following ligand binding and nuclear translocation, which may provide partial explanation for some clinical drug interactions.

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance

CYP2D6 phenotyping and genotyping appear to be useful in predicting steady-state concentrations of some classical antipsychotic drugs, but their usefulness in predicting clinical effects must be explored.

Polymorphism of human cytochrome P450 enzymes and its clinical impact

Current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) is highlighted to understand the large interindividual variability in drug clearance and responses in clinical practice and to improve the efficacy and safety of both prospective and currently available drugs.

A Fatal Doxepin Poisoning Associated With a Defective CYP2D6 Genotype

This case strongly emphasizes that a pharmacogenetic analysis in postmortem forensic setting may reveal new insight to the cause or manner of death of postmortem toxicology cases of fatal drug poisonings related to CYP2D6 substrates.

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.

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

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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.

Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro.

Tranylcypromine [particularly R-(+) isomer], tryptamine, and methoxsalen are specific and relatively selective for CYP2A6 and may be useful in vivo to decrease smoking by inhibiting nicotine metabolism with a low risk of metabolic drug interactions.

Geometric isomerization of doxepin during its N-demethylation in humans.

Findings indicate that isomerization occurs during the N-demethylation of doxepin, possibly involving the formation of an intermediate in which the exocyclic double bond is hydrated and then subseqently dehydrated.

Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate.

The present study directly proved that the chemopreventive effects of PEITC for nitrosamine-induced carcinogenesis are due to the inhibition of CYP by an in vitro study.

Stereoselective in vivo and in vitro studies on the metabolism of doxepin and N-desmethyldoxepin.

In vitro data suggested that the distortion of the Z:E ratio of N-desmethyldoxepin was a consequence of faster metabolism of the E-isomer in comparison with Z-N-desMethyld Oxepin rather than 'enrichment' of theZ-isomers at the expense of theE-isome.

Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily.

  • S. OnoT. Hatanaka T. Satoh
  • Biology, Chemistry
    Xenobiotica; the fate of foreign compounds in biological systems
  • 1996
In the human liver, the metabolism of diazepam to nordiazepam is mediated by CYP3A4, which is reported as the most abundant P450 form in human liver as well as 2C19, which has been reported as a polymorphic enzyme.

Fluvoxamine is a potent inhibitor of cytochrome P4501A2.

The mephenytoin oxidation polymorphism is partially responsible for the N‐demethylation of imipramine

In conclusion, this and an earlier study show that the oxidation of imipramine is mediated by means of two different polymorphic P450 isozymes, 2‐hydroxylation by way of the sparteine oxygenase (P450IID6) and demethylation by Way of the mephenytoin oxygen enzyme (P 450IIC8).

Distribution and metabolism of doxepin.

  • D. Hobbs
  • Chemistry, Biology
    Biochemical pharmacology
  • 1969

Stereoselective pharmacokinetics of doxepin isomers

Results for total doxepin showed wide intersubject variation in all pharmacokinetic parameters except tmax and Cmax and the areas under the plasma concentration versus time curves (AUC) of cis-N-desmethyldoxepin were significantly higher than those of the corresponding trans-isomer.