The role of cytochrome P450 2D6 in the metabolism of moclobemide

Härtter, Sebastian; Dingemanse, Jasper; Baier, Dieter; Ziegler, G.; Hiemke, Christoph

doi:10.1016/0924-977x(96)00023-5

Cited by 21 publications

(14 citation statements)

References 22 publications

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“…5). Such chemicals are rather poor substrates for CYP2D6, such as moclobemide (Härtter et al, 1996), nateglinide, leflunomide, lidocaine, and flutamide. Poor catalysis was also detected with sulfoxides, such as (S/R)-omeprazole and lansoprazole.…”

Section: Dual Template Mimicking System To Predict Cyp2d6 Metabolismmentioning

confidence: 99%

Unimolecular and Bimolecular Binding System for the Prediction of CYP2D6-Mediated Metabolism

Sato¹,

Yamazoe²

2011

Drug Metab Dispos

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ABSTRACT:We have developed a template system for the prediction of CYP2D6-mediated metabolism of compounds. The system is composed of two types of two-dimensional templates (templates A and B), which were generated from mutually occupied areas of typical CYP2D6 substrates. The areas of templates are expressed as hexagonal blocks for application to the two-dimensional structures of chemicals. Experiments with 93 reactions with 69 typical substrates indicated the necessity for two similar but distinct shapes for template A (A1 and A2) for optimal placement. A frequently occupied area for substrates in template A1 was defined as a trigger area in which to capture a substrate for initiation of metabolism. Another frequently occupied area was found near the site of metabolism in template B. Both frequently occupied areas are linked to a pinching area. Occupancy of substrates on two template areas is suggested to be essential for the metabolism of CYPD6 substrates. In cases of CYP2D6 substrates without simultaneous occupancy of both areas, bimolecular placement, in which two molecules are placed coordinately, is proposed. Metabolism of small molecules, including naphthalene and quinoline, became explainable with the use of this idea. Validation of this template system with the use of both good and poor CYP2D6 substrates indicated clear advantages of the present system as a tool for drug modification, in addition to enabling highly accurate estimation of the site of metabolism.

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Section: Dual Template Mimicking System To Predict Cyp2d6 Metabolismmentioning

confidence: 99%

Unimolecular and Bimolecular Binding System for the Prediction of CYP2D6-Mediated Metabolism

Sato¹,

Yamazoe²

2011

Drug Metab Dispos

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“…37,[83][84][85][86]129,130 Venlafaxine is a chiral drug with both enantiomers transformed by CYP2D6 to the equipotent O-desmethyl-venlafaxine. 88,90,131 Thus, the active drug moiety, sum of parent drug and metabolite is not much changed by the CYP2D6 genotype.…”

Section: Impact Of Cyp2d6 Polymorphisms On Dosing Of Antidepressantsmentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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“…25,26 Finally, CYP2D6 polymorphism seems to have no major influence on metabolism of nefazodone, moclobemide, reboxetine and trazodone. [27][28][29][30][31][32][33] Possible clinical implications The question whether the differences in pharmacokinetic parameters caused by genetic polymorphisms in DMEs really impact the outcome of antidepressant treatment has been studied in some observational studies. In a German study evaluating the effect of CYP2D6 genotype on treatment with CYP2D6-dependent antidepressants, PMs and UMs were significantly overrepresented as compared to the control population, respectively, in the group of patients suffering from adverse drug reactions (fourfold) and nonresponders (fivefold).…”

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confidence: 99%