Role of cytochrome P4502D6 in the metabolism of brofaromine : a new selective MAO-A inhibitor
The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine...
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Veröffentlicht in: | European journal of clinical pharmacology 1993-10, Vol.45 (3), p.265-269 |
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container_title | European journal of clinical pharmacology |
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creator | FEIFEL, N KUCHER, K FUCHS, L JEDRYCHOWSKI, M SCHMIDT, E ANTONIN, K.-H BIECK, P. R GLEITER, C. H |
description | The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine. |
doi_str_mv | 10.1007/BF00315394 |
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R ; GLEITER, C. H</creator><creatorcontrib>FEIFEL, N ; KUCHER, K ; FUCHS, L ; JEDRYCHOWSKI, M ; SCHMIDT, E ; ANTONIN, K.-H ; BIECK, P. R ; GLEITER, C. H</creatorcontrib><description>The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/BF00315394</identifier><identifier>PMID: 8276052</identifier><language>eng</language><publisher>Heidelberg: Springer</publisher><subject>Adult ; Biological and medical sciences ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - metabolism ; Cytochrome P-450 Enzyme System - urine ; Female ; Humans ; Male ; Medical sciences ; Mixed Function Oxygenases - antagonists & inhibitors ; Mixed Function Oxygenases - metabolism ; Mixed Function Oxygenases - urine ; Monoamine Oxidase Inhibitors - blood ; Monoamine Oxidase Inhibitors - metabolism ; Monoamine Oxidase Inhibitors - urine ; Neuropharmacology ; Pharmacology. Drug treatments ; Phenotype ; Piperidines - blood ; Piperidines - metabolism ; Piperidines - pharmacokinetics ; Piperidines - urine ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. 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R</creatorcontrib><creatorcontrib>GLEITER, C. H</creatorcontrib><title>Role of cytochrome P4502D6 in the metabolism of brofaromine : a new selective MAO-A inhibitor</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><description>The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.</description><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 CYP2D6</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Cytochrome P-450 Enzyme System - urine</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mixed Function Oxygenases - antagonists & inhibitors</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Mixed Function Oxygenases - urine</subject><subject>Monoamine Oxidase Inhibitors - blood</subject><subject>Monoamine Oxidase Inhibitors - metabolism</subject><subject>Monoamine Oxidase Inhibitors - urine</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenotype</subject><subject>Piperidines - blood</subject><subject>Piperidines - metabolism</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - urine</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Quinidine - administration & dosage</subject><subject>Quinidine - pharmacology</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0E1LxDAQBuAgiq6rF-9CDuJBqE4-mrTe1o9VQVkRPUpJs1M20jZr0lX239vFoqeBeZ-Zw0vIEYNzBqAvrqYAgqUil1tkxKTgCQPJtslos05UrmGP7Mf4AcDSHMQu2c24VpDyEXl_8TVSX1G77rxdBN8gfZYp8BtFXUu7BdIGO1P62sVm48rgK9Mz1yK9pIa2-E0j1mg794X0aTJLJv3hwpWu8-GA7FSmjng4zDF5m96-Xt8nj7O7h-vJY2K5hi5hMsVMKo454wKYtFZbNVdSgjIs5yVnimVzpTJZGZ1JrPJSo7QmNbYEJowYk9Pfv8vgP1cYu6Jx0WJdmxb9KhZaMamEzHp49gtt8DEGrIplcI0J64JBsemy-O-yx8fD11XZ4PyPDuX1-cmQm2hNXQXTWhf_mNBSp1KIHzIBeB4</recordid><startdate>19931001</startdate><enddate>19931001</enddate><creator>FEIFEL, N</creator><creator>KUCHER, K</creator><creator>FUCHS, L</creator><creator>JEDRYCHOWSKI, M</creator><creator>SCHMIDT, E</creator><creator>ANTONIN, K.-H</creator><creator>BIECK, P. 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Drug treatments</topic><topic>Phenotype</topic><topic>Piperidines - blood</topic><topic>Piperidines - metabolism</topic><topic>Piperidines - pharmacokinetics</topic><topic>Piperidines - urine</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Quinidine - administration & dosage</topic><topic>Quinidine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>FEIFEL, N</creatorcontrib><creatorcontrib>KUCHER, K</creatorcontrib><creatorcontrib>FUCHS, L</creatorcontrib><creatorcontrib>JEDRYCHOWSKI, M</creatorcontrib><creatorcontrib>SCHMIDT, E</creatorcontrib><creatorcontrib>ANTONIN, K.-H</creatorcontrib><creatorcontrib>BIECK, P. R</creatorcontrib><creatorcontrib>GLEITER, C. 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Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.</abstract><cop>Heidelberg</cop><cop>Berlin</cop><pub>Springer</pub><pmid>8276052</pmid><doi>10.1007/BF00315394</doi><tpages>5</tpages></addata></record> |
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subjects | Adult Biological and medical sciences Cytochrome P-450 CYP2D6 Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism Cytochrome P-450 Enzyme System - urine Female Humans Male Medical sciences Mixed Function Oxygenases - antagonists & inhibitors Mixed Function Oxygenases - metabolism Mixed Function Oxygenases - urine Monoamine Oxidase Inhibitors - blood Monoamine Oxidase Inhibitors - metabolism Monoamine Oxidase Inhibitors - urine Neuropharmacology Pharmacology. Drug treatments Phenotype Piperidines - blood Piperidines - metabolism Piperidines - pharmacokinetics Piperidines - urine Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Quinidine - administration & dosage Quinidine - pharmacology |
title | Role of cytochrome P4502D6 in the metabolism of brofaromine : a new selective MAO-A inhibitor |
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