MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?

In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical s...

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Detalles Bibliográficos
Autores: Torre Fornell, Rafael de la, Yubero Lahoz, Samanta, 1985-, Pardo Lozano, Ricardo, Farré Albaladejo, Magí
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/23759
Acceso en línea:http://hdl.handle.net/10230/23759
http://dx.doi.org/10.3389/fgene.2012.00235
Access Level:acceso abierto
Palabra clave:MDMA (Droga) -- Farmacocinètica
MDMA (Droga) -- Metabolisme
Medicaments -- Interacció
MDMA
CYP2D6
Methamphetamine
Pharmacogenetics
Ecstasy
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network_acronym_str ES
network_name_str España
repository_id_str
spelling MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?Torre Fornell, Rafael de laYubero Lahoz, Samanta, 1985-Pardo Lozano, RicardoFarré Albaladejo, MagíMDMA (Droga) -- FarmacocinèticaMDMA (Droga) -- MetabolismeMedicaments -- InteraccióMDMACYP2D6MethamphetaminePharmacogeneticsEcstasyIn vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI) of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer (PM) phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies.Yubero-Lahoz S, Pardo-Lozano R, Farré MFrontiers201520152012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/23759http://dx.doi.org/10.3389/fgene.2012.00235reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésFrontiers in Genetics. 2012;3:235© 2012 de la Torre, Yubero-Lahoz, Pardo-Lozano and Farré. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.https://creativecommons.org/licenses/by/3.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/237592026-05-29T05:05:01Z
dc.title.none.fl_str_mv MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
title MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
spellingShingle MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
Torre Fornell, Rafael de la
MDMA (Droga) -- Farmacocinètica
MDMA (Droga) -- Metabolisme
Medicaments -- Interacció
MDMA
CYP2D6
Methamphetamine
Pharmacogenetics
Ecstasy
title_short MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
title_full MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
title_fullStr MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
title_full_unstemmed MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
title_sort MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?
dc.creator.none.fl_str_mv Torre Fornell, Rafael de la
Yubero Lahoz, Samanta, 1985-
Pardo Lozano, Ricardo
Farré Albaladejo, Magí
author Torre Fornell, Rafael de la
author_facet Torre Fornell, Rafael de la
Yubero Lahoz, Samanta, 1985-
Pardo Lozano, Ricardo
Farré Albaladejo, Magí
author_role author
author2 Yubero Lahoz, Samanta, 1985-
Pardo Lozano, Ricardo
Farré Albaladejo, Magí
author2_role author
author
author
dc.subject.none.fl_str_mv MDMA (Droga) -- Farmacocinètica
MDMA (Droga) -- Metabolisme
Medicaments -- Interacció
MDMA
CYP2D6
Methamphetamine
Pharmacogenetics
Ecstasy
topic MDMA (Droga) -- Farmacocinètica
MDMA (Droga) -- Metabolisme
Medicaments -- Interacció
MDMA
CYP2D6
Methamphetamine
Pharmacogenetics
Ecstasy
description In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI) of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer (PM) phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies.Yubero-Lahoz S, Pardo-Lozano R, Farré M
publishDate 2012
dc.date.none.fl_str_mv 2012
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/23759
http://dx.doi.org/10.3389/fgene.2012.00235
url http://hdl.handle.net/10230/23759
http://dx.doi.org/10.3389/fgene.2012.00235
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Frontiers in Genetics. 2012;3:235
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers
publisher.none.fl_str_mv Frontiers
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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