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Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics

Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse...

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Autores principales: Zubiaur, Pablo, Fernández-Campos, Paula, Navares-Gómez, Marcos, Soria-Chacartegui, Paula, Villapalos-García, Gonzalo, Román, Manuel, Mejía-Abril, Gina, Ochoa, Dolores, Abad-Santos, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540141/
https://www.ncbi.nlm.nih.gov/pubmed/34683865
http://dx.doi.org/10.3390/pharmaceutics13101573
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author Zubiaur, Pablo
Fernández-Campos, Paula
Navares-Gómez, Marcos
Soria-Chacartegui, Paula
Villapalos-García, Gonzalo
Román, Manuel
Mejía-Abril, Gina
Ochoa, Dolores
Abad-Santos, Francisco
author_facet Zubiaur, Pablo
Fernández-Campos, Paula
Navares-Gómez, Marcos
Soria-Chacartegui, Paula
Villapalos-García, Gonzalo
Román, Manuel
Mejía-Abril, Gina
Ochoa, Dolores
Abad-Santos, Francisco
author_sort Zubiaur, Pablo
collection PubMed
description Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase (COMT), other enzymes (e.g., UGT1A1 or UGT1A4), and transporters (e.g., SLCO1B1, ABCB1, or ABCG2). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine’s metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings.
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spelling pubmed-85401412021-10-24 Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics Zubiaur, Pablo Fernández-Campos, Paula Navares-Gómez, Marcos Soria-Chacartegui, Paula Villapalos-García, Gonzalo Román, Manuel Mejía-Abril, Gina Ochoa, Dolores Abad-Santos, Francisco Pharmaceutics Article Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase (COMT), other enzymes (e.g., UGT1A1 or UGT1A4), and transporters (e.g., SLCO1B1, ABCB1, or ABCG2). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine’s metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings. MDPI 2021-09-28 /pmc/articles/PMC8540141/ /pubmed/34683865 http://dx.doi.org/10.3390/pharmaceutics13101573 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zubiaur, Pablo
Fernández-Campos, Paula
Navares-Gómez, Marcos
Soria-Chacartegui, Paula
Villapalos-García, Gonzalo
Román, Manuel
Mejía-Abril, Gina
Ochoa, Dolores
Abad-Santos, Francisco
Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics
title Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics
title_full Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics
title_fullStr Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics
title_full_unstemmed Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics
title_short Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics
title_sort variants in comt, cyp3a5, cyp2b6, and abcg2 alter quetiapine pharmacokinetics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540141/
https://www.ncbi.nlm.nih.gov/pubmed/34683865
http://dx.doi.org/10.3390/pharmaceutics13101573
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