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CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy
PURPOSE: To perform therapeutic drug monitoring (TDM) of total and free plasma valproic acid (VPA) concentrations in pediatric patients with epilepsy and to analyze related factors. PATIENTS AND METHODS: Pediatric epileptic patients treated in 2015–2019 in our hospital were assessed. Total and free...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043849/ https://www.ncbi.nlm.nih.gov/pubmed/33859491 http://dx.doi.org/10.2147/PGPM.S301893 |
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author | Wu, Xikun Dong, Weichong Li, Haoran Yang, Xiuling Jin, Yiran Zhang, Zhiqing Jiang, Ye |
author_facet | Wu, Xikun Dong, Weichong Li, Haoran Yang, Xiuling Jin, Yiran Zhang, Zhiqing Jiang, Ye |
author_sort | Wu, Xikun |
collection | PubMed |
description | PURPOSE: To perform therapeutic drug monitoring (TDM) of total and free plasma valproic acid (VPA) concentrations in pediatric patients with epilepsy and to analyze related factors. PATIENTS AND METHODS: Pediatric epileptic patients treated in 2015–2019 in our hospital were assessed. Total and free plasma VPA concentrations were obtained by UPLC and LC-MS/MS, respectively. Regression analysis was performed to examine the associations of free plasma VPA with total plasma VPA and plasma protein binding rate. The impacts of individual situation, CYP2C9 genotype, and drug combination on VPA concentration were examined. RESULTS: Of the 251 patients, 81 had lower total concentrations than effective therapeutic levels; 86 and 31 patients had infections and central nervous system dysplasia, respectively. VPA’s daily doses and free drug concentrations were significantly lower in the CYP2C9 *3/*3 genotype group versus the CYP2C9 *1/*3 and CYP2C9 *1/*1 groups (P<0.05). Free and total VPA concentrations were linked by Y = 0.0004 X(2) + 0.042 X + 0.3035 (r=0.6981); VPA plasma protein binding rate and free VPA concentration were related by Y = 0.0003 X(2) - 0.0127 X + 0.9777 (r=0.8136). Both total and free VPA concentrations were significantly decreased in patients simultaneously administered phenobarbital, meropenem and biapenem (P<0.05), with therapeutic failure after meropenem/biapenem co-administration. CONCLUSION: Free VPA amounts have nonlinear relationships with total VPA amounts and plasma protein binding rate in epileptic children. Additionally, CYP2C9 *3/*3 expression affects VPA metabolism. Since phenobarbital affects VPA metabolism, TDM is recommended. Meanwhile, carbapenem-co-administration with VPA should be prohibited. |
format | Online Article Text |
id | pubmed-8043849 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-80438492021-04-14 CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy Wu, Xikun Dong, Weichong Li, Haoran Yang, Xiuling Jin, Yiran Zhang, Zhiqing Jiang, Ye Pharmgenomics Pers Med Original Research PURPOSE: To perform therapeutic drug monitoring (TDM) of total and free plasma valproic acid (VPA) concentrations in pediatric patients with epilepsy and to analyze related factors. PATIENTS AND METHODS: Pediatric epileptic patients treated in 2015–2019 in our hospital were assessed. Total and free plasma VPA concentrations were obtained by UPLC and LC-MS/MS, respectively. Regression analysis was performed to examine the associations of free plasma VPA with total plasma VPA and plasma protein binding rate. The impacts of individual situation, CYP2C9 genotype, and drug combination on VPA concentration were examined. RESULTS: Of the 251 patients, 81 had lower total concentrations than effective therapeutic levels; 86 and 31 patients had infections and central nervous system dysplasia, respectively. VPA’s daily doses and free drug concentrations were significantly lower in the CYP2C9 *3/*3 genotype group versus the CYP2C9 *1/*3 and CYP2C9 *1/*1 groups (P<0.05). Free and total VPA concentrations were linked by Y = 0.0004 X(2) + 0.042 X + 0.3035 (r=0.6981); VPA plasma protein binding rate and free VPA concentration were related by Y = 0.0003 X(2) - 0.0127 X + 0.9777 (r=0.8136). Both total and free VPA concentrations were significantly decreased in patients simultaneously administered phenobarbital, meropenem and biapenem (P<0.05), with therapeutic failure after meropenem/biapenem co-administration. CONCLUSION: Free VPA amounts have nonlinear relationships with total VPA amounts and plasma protein binding rate in epileptic children. Additionally, CYP2C9 *3/*3 expression affects VPA metabolism. Since phenobarbital affects VPA metabolism, TDM is recommended. Meanwhile, carbapenem-co-administration with VPA should be prohibited. Dove 2021-04-09 /pmc/articles/PMC8043849/ /pubmed/33859491 http://dx.doi.org/10.2147/PGPM.S301893 Text en © 2021 Wu et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Wu, Xikun Dong, Weichong Li, Haoran Yang, Xiuling Jin, Yiran Zhang, Zhiqing Jiang, Ye CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy |
title | CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy |
title_full | CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy |
title_fullStr | CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy |
title_full_unstemmed | CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy |
title_short | CYP2C9*3/*3 Gene Expression Affects the Total and Free Concentrations of Valproic Acid in Pediatric Patients with Epilepsy |
title_sort | cyp2c9*3/*3 gene expression affects the total and free concentrations of valproic acid in pediatric patients with epilepsy |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043849/ https://www.ncbi.nlm.nih.gov/pubmed/33859491 http://dx.doi.org/10.2147/PGPM.S301893 |
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