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

@article{Hrtter2004TheNO,
  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},
  year={2004},
  volume={19},
  pages={1034-1037}
}
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… 

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References

SHOWING 1-10 OF 16 REFERENCES

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

TLDR
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.

TLDR
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.

TLDR
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.

TLDR
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.

TLDR
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
TLDR
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

TLDR
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

TLDR
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.