Role of cytochrome P4502D6 in the metabolism of brofaromine

Feifel, N.; Kucher, Klaus; Fuchs, Luiz Fernando Portugal; Jedrychowski, M.; Schmidt, Ellen; Antonin, K. H.; Bieck, P. R.; Ch, Gleiter

doi:10.1007/bf00315394

Cited by 18 publications

(7 citation statements)

References 13 publications

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“…43 . The intrinsic reactivity of the site of metabolism (4.7 kcal/mol) is very close to those of sites on the aromatic rings (non sites of metabolism, 3.3–4.9 kcal/mol) (Figure 18).…”

Section: Resultsmentioning

confidence: 99%

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IDSite: An Accurate Approach to Predict P450-Mediated Drug Metabolism

Schneebeli

Bylund

et al. 2011

J. Chem. Theory Comput.

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Accurate prediction of drug metabolism is crucial for drug design. Since a large majority of drugs metabolism involves P450 enzymes, we herein describe a computational approach, IDSite, to predict P450-mediated drug metabolism. To model induced-fit effects, IDSite samples the conformational space with flexible docking in Glide followed by two refinement stages using the Protein Local Optimization Program (PLOP). Sites of metabolism (SOMs) are predicted according to a physical-based score that evaluates the potential of atoms to react with the catalytic iron center. As a preliminary test, we present in this paper the prediction of hydroxylation and O-dealkylation sites mediated by CYP2D6 using two different models: a physical-based simulation model, and a modification of this model in which a small number of parameters are fit to a training set. Without fitting any parameters to experimental data, the Physical IDSite scoring recovers 83% of the experimental observations for 56 compounds with a very low false positive rate. With only 4 fitted parameters, the Fitted IDSite was trained with the subset of 36 compounds and successfully applied to the other 20 compounds, recovering 94% of the experimental observations with high sensitivity and specificity for both sets.

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“…43 . The intrinsic reactivity of the site of metabolism (4.7 kcal/mol) is very close to those of sites on the aromatic rings (non sites of metabolism, 3.3–4.9 kcal/mol) (Figure 18).…”

Section: Resultsmentioning

confidence: 99%

“…The first case we discuss is brofaromine, for which experiments show that the major metabolic pathway is O-demethylation mediated by CYP2D6 . The intrinsic reactivity of the site of metabolism (4.7 kcal/mol) is very close to those of sites on the aromatic rings (nonsites of metabolism, 3.3–4.9 kcal/mol; Figure ).…”

Section: Resultsmentioning

confidence: 99%

IDSite: An Accurate Approach to Predict P450-Mediated Drug Metabolism

Schneebeli

Bylund

et al. 2011

J. Chem. Theory Comput.

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“…This fact may cause clinical implications as drugs like the antiarrhythmic quinidine may block this cytochrome isoenzyme and convert EM of debrisoquine into phenocopies of PM. Thus, quinidine or other drugs blocking the same cytochrome isoenzyme may alter brofaromine pharmacokinetics when coadministered (Feifel et al, 1993). The clinical relevance of this finding should be carefully evaluated in patients on longterm treatment since the published data were obtained using single doses of brofaromine in a panel of young healthy volunteers.…”

Section: Drug Interactionsmentioning

confidence: 89%

“…A recent study by Feifel et al (1993) pared to extensive metabolizers of debrisoquine (EM), poor metabolizers of debrisoquine (PM) had significantly longer T1/2 (136%) and a larger AUC (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (40%) of its primary metabolite O-desmethyl-brofaromine (CGP 35 748). The mean metabolite/substrate i:atio was about 6 times greater in EM than in PM.…”

Section: Serum Protein Binding Metabolism Excretionmentioning

confidence: 99%

“…The rapid reduction in pressure sensitivity after the discontinuation of brofaromine treatment provides evidence of the reversibility of MAO inhibition. 6.1.2 Cytochrome P450 interactions Feifel et al (1993) have shown that cytochrome P4502D6 has a role in the metabolism of brofaromine. This fact may cause clinical implications as drugs like the antiarrhythmic quinidine may block this cytochrome isoenzyme and convert EM of debrisoquine into phenocopies of PM.…”

Section: Drug Interactionsmentioning

confidence: 99%

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Brofaromine ? a review of its pharmacological properties and therapeutic use

Volz

Gleiter

Waldmeier³

et al. 1996

J. Neural Transmission

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The antidepressant activity of monoamine oxidase inhibitors has been well established for 30 years. Nevertheless, this group of compounds was handled with great care, mainly because of the interaction potential with tyramine-containing foodstuff. With the discovery of reversible and selective inhibitors of monoamine oxidase type A a renaissance of these compounds has begun. In this paper one of these new substances--brofaromine--will be described in detail. Biochemical and pharmacological aspects will be reviewed, showing that brofaromine is a selective and reversible inhibitor of monoamine oxidase type A with additional serotonin reuptake inhibiting properties. Both mechanisms of action may synergize in the antidepressant effect of the compound. The main results of clinical trials in depression and other indication areas will also be covered. Special attention will be put on the side effect profile.

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