Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam
Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pha...
| Autores: | , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/714733 |
| Acceso en línea: | http://hdl.handle.net/10486/714733 https://dx.doi.org/10.1016/j.biopha.2022.113747 |
| Access Level: | acceso abierto |
| Palabra clave: | CYP2B6 CYP2C19 Diazepam Pharmacogenetics Farmacia Medicina |
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Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepamZubiaur Precioso, PabloSoria Chacartegui, PaulaOchoa Mazarro, María DoloresFigueiredo-Tor, LauraVillapalos-García, GonzaloNavares-Gómez, MarcosNovalbos, JesúsMatas, MiriamCalleja, SofíaMejía Abril, GinaRomán, ManuelAbad Santos, FranciscoCYP2B6CYP2C19DiazepamPharmacogeneticsFarmaciaMedicinaDiazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pharmacogenetic candidate biomarkers. In this work, we aimed to explore the impact of CYP3A4 and CYP2C19 phenotypes and of 99 additional variants in other 31 pharmacogenes (including other CYP, UGT, NAT2 and CES enzymes, ABC and SLC transporters) on diazepam pharmacokinetic variability and safety. 30 healthy volunteers that had participated in a single-dose bioequivalence clinical trial of two diazepam formulations were enrolled in the present candidate gene pharmacogenetic study. CYP2C19 poor metabolizers (PMs) showed an almost 2-fold increase in AUC0-∞/DW compared to rapid (RMs) or normal (NM) metabolizers, and a 1.46-fold increase compared to intermediate metabolizers (IMs). CYP2B6 PMs showed a 2,74-fold higher AUC0-∞/DW compared to RMs, and 2.10-fold compared to NMs (p < 0.007). A dose reduction of 25–50 % may be appropriate for CYP2C19 or CYP2B6 PMs to avoid ADRs, dependence and tolerance. Combined CYP2C19 +CYP2B6 PMs may not use diazepam or sharper dose adjustments (e.g., a dose reduction of 50–70 %) may be advisable. To our knowledge, this is the first work to report a strong relationship between CYP2B6 phenotype and diazepam pharmacokinetics. Additional nominal associations (i.e., 0.007 <p < 0.05) between ABCG2, ABCB1, NAT2 and UGT1A4 polymorphisms and pharmacokinetic variability were observed; further research should elaborate on the clinical relevance of the described associationsElsevierDepartamento de FarmacologíaFacultad de Medicina20222022-11-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/714733https://dx.doi.org/10.1016/j.biopha.2022.113747reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7147332026-06-23T12:46:27Z |
| dc.title.none.fl_str_mv |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam |
| title |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam |
| spellingShingle |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam Zubiaur Precioso, Pablo CYP2B6 CYP2C19 Diazepam Pharmacogenetics Farmacia Medicina |
| title_short |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam |
| title_full |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam |
| title_fullStr |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam |
| title_full_unstemmed |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam |
| title_sort |
Association between CYP2C19 and CYP2B6 phenotypes and the pharmacokinetics and safety of diazepam |
| dc.creator.none.fl_str_mv |
Zubiaur Precioso, Pablo Soria Chacartegui, Paula Ochoa Mazarro, María Dolores Figueiredo-Tor, Laura Villapalos-García, Gonzalo Navares-Gómez, Marcos Novalbos, Jesús Matas, Miriam Calleja, Sofía Mejía Abril, Gina Román, Manuel Abad Santos, Francisco |
| author |
Zubiaur Precioso, Pablo |
| author_facet |
Zubiaur Precioso, Pablo Soria Chacartegui, Paula Ochoa Mazarro, María Dolores Figueiredo-Tor, Laura Villapalos-García, Gonzalo Navares-Gómez, Marcos Novalbos, Jesús Matas, Miriam Calleja, Sofía Mejía Abril, Gina Román, Manuel Abad Santos, Francisco |
| author_role |
author |
| author2 |
Soria Chacartegui, Paula Ochoa Mazarro, María Dolores Figueiredo-Tor, Laura Villapalos-García, Gonzalo Navares-Gómez, Marcos Novalbos, Jesús Matas, Miriam Calleja, Sofía Mejía Abril, Gina Román, Manuel Abad Santos, Francisco |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Departamento de Farmacología Facultad de Medicina |
| dc.subject.none.fl_str_mv |
CYP2B6 CYP2C19 Diazepam Pharmacogenetics Farmacia Medicina |
| topic |
CYP2B6 CYP2C19 Diazepam Pharmacogenetics Farmacia Medicina |
| description |
Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pharmacogenetic candidate biomarkers. In this work, we aimed to explore the impact of CYP3A4 and CYP2C19 phenotypes and of 99 additional variants in other 31 pharmacogenes (including other CYP, UGT, NAT2 and CES enzymes, ABC and SLC transporters) on diazepam pharmacokinetic variability and safety. 30 healthy volunteers that had participated in a single-dose bioequivalence clinical trial of two diazepam formulations were enrolled in the present candidate gene pharmacogenetic study. CYP2C19 poor metabolizers (PMs) showed an almost 2-fold increase in AUC0-∞/DW compared to rapid (RMs) or normal (NM) metabolizers, and a 1.46-fold increase compared to intermediate metabolizers (IMs). CYP2B6 PMs showed a 2,74-fold higher AUC0-∞/DW compared to RMs, and 2.10-fold compared to NMs (p < 0.007). A dose reduction of 25–50 % may be appropriate for CYP2C19 or CYP2B6 PMs to avoid ADRs, dependence and tolerance. Combined CYP2C19 +CYP2B6 PMs may not use diazepam or sharper dose adjustments (e.g., a dose reduction of 50–70 %) may be advisable. To our knowledge, this is the first work to report a strong relationship between CYP2B6 phenotype and diazepam pharmacokinetics. Additional nominal associations (i.e., 0.007 <p < 0.05) between ABCG2, ABCB1, NAT2 and UGT1A4 polymorphisms and pharmacokinetic variability were observed; further research should elaborate on the clinical relevance of the described associations |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022-11-01 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10486/714733 https://dx.doi.org/10.1016/j.biopha.2022.113747 |
| url |
http://hdl.handle.net/10486/714733 https://dx.doi.org/10.1016/j.biopha.2022.113747 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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Elsevier |
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Elsevier |
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Universidad Autónoma de Madrid |
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