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Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine
Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934922/ https://www.ncbi.nlm.nih.gov/pubmed/36817149 http://dx.doi.org/10.3389/fphar.2023.1110460 |
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author | Calleja, Sofía Zubiaur, Pablo Ochoa, Dolores Villapalos-García, Gonzalo Mejia-Abril, Gina Soria-Chacartegui, Paula Navares-Gómez, Marcos de Miguel, Alejandro Román, Manuel Martín-Vílchez, Samuel Abad-Santos, Francisco |
author_facet | Calleja, Sofía Zubiaur, Pablo Ochoa, Dolores Villapalos-García, Gonzalo Mejia-Abril, Gina Soria-Chacartegui, Paula Navares-Gómez, Marcos de Miguel, Alejandro Román, Manuel Martín-Vílchez, Samuel Abad-Santos, Francisco |
author_sort | Calleja, Sofía |
collection | PubMed |
description | Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent. |
format | Online Article Text |
id | pubmed-9934922 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99349222023-02-17 Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine Calleja, Sofía Zubiaur, Pablo Ochoa, Dolores Villapalos-García, Gonzalo Mejia-Abril, Gina Soria-Chacartegui, Paula Navares-Gómez, Marcos de Miguel, Alejandro Román, Manuel Martín-Vílchez, Samuel Abad-Santos, Francisco Front Pharmacol Pharmacology Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent. Frontiers Media S.A. 2023-02-02 /pmc/articles/PMC9934922/ /pubmed/36817149 http://dx.doi.org/10.3389/fphar.2023.1110460 Text en Copyright © 2023 Calleja, Zubiaur, Ochoa, Villapalos-García, Mejia-Abril, Soria-Chacartegui, Navares-Gómez, de Miguel, Román, Martín-Vílchez and Abad-Santos. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Calleja, Sofía Zubiaur, Pablo Ochoa, Dolores Villapalos-García, Gonzalo Mejia-Abril, Gina Soria-Chacartegui, Paula Navares-Gómez, Marcos de Miguel, Alejandro Román, Manuel Martín-Vílchez, Samuel Abad-Santos, Francisco Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine |
title | Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine |
title_full | Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine |
title_fullStr | Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine |
title_full_unstemmed | Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine |
title_short | Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine |
title_sort | impact of polymorphisms in cyp and ugt enzymes and abc and slco1b1 transporters on the pharmacokinetics and safety of desvenlafaxine |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934922/ https://www.ncbi.nlm.nih.gov/pubmed/36817149 http://dx.doi.org/10.3389/fphar.2023.1110460 |
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