Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset
Background: The analysis of substrates of polymorphic cytochrome P450 (CYP) enzymes is important information to enable drug–drug interactions (DDIs) analysis and the relevance of pharmacogenetics in this context in large datasets. Our aim was to compare different approaches to assess the substrate p...
| Autores principales: | , , , , , |
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| Formato: | Artículo |
| Lenguaje: | English |
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MDPI AG
2024-01-01
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| Colección: | Biomedicines |
| Materias: | |
| Acceso en línea: | https://www.mdpi.com/2227-9059/12/1/161 |
| _version_ | 1827369751659151360 |
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| author | Jakob Sommer Justyna Wozniak Judith Schmitt Jana Koch Julia C. Stingl Katja S. Just |
| author_facet | Jakob Sommer Justyna Wozniak Judith Schmitt Jana Koch Julia C. Stingl Katja S. Just |
| author_sort | Jakob Sommer |
| collection | DOAJ |
| description | Background: The analysis of substrates of polymorphic cytochrome P450 (CYP) enzymes is important information to enable drug–drug interactions (DDIs) analysis and the relevance of pharmacogenetics in this context in large datasets. Our aim was to compare different approaches to assess the substrate properties of drugs for certain polymorphic CYP2 enzymes. Methods: A standardized manual method and an automatic method were developed and compared to assess the substrate properties for the metabolism of drugs by CYP2D6, 2C9, and 2C19. The automatic method used a matching approach to three freely available resources. We applied the manual and automatic methods to a large real-world dataset deriving from a prospective multicenter study collecting adverse drug reactions in emergency departments in Germany (ADRED). Results: In total, 23,878 medication entries relating to 895 different drugs were analyzed in the real-world dataset. The manual method was able to assess 12.2% (<i>n</i> = 109) of drugs, and the automatic method between 12.1% (<i>n</i> = 109) and 88.9% (<i>n</i> = 796), depending on the resource used. The CYP substrate classifications demonstrated moderate to almost perfect agreements for CYP2D6 and CYP2C19 (Cohen’s Kappa (κ) 0.48–0.90) and fair to moderate agreements for CYP2C9 (κ 0.20–0.48). Conclusion: A closer look at different classifications between methods revealed that both methods are prone to error in different ways. While the automated method excels in time efficiency, completeness, and actuality, the manual method might be better able to identify CYP2 substrates with clinical relevance. |
| first_indexed | 2024-03-08T09:57:03Z |
| format | Article |
| id | doaj.art-a031389b7cb84d65b9d788a4da58d5f7 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-08T09:57:03Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-a031389b7cb84d65b9d788a4da58d5f72024-01-29T13:47:38ZengMDPI AGBiomedicines2227-90592024-01-0112116110.3390/biomedicines12010161Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale DatasetJakob Sommer0Justyna Wozniak1Judith Schmitt2Jana Koch3Julia C. Stingl4Katja S. Just5Institute of Clinical Pharmacology, University Hospital of RWTH Aachen, 52074 Aachen, GermanyInstitute of Clinical Pharmacology, University Hospital of RWTH Aachen, 52074 Aachen, GermanyInstitute of Clinical Pharmacology, University Hospital of RWTH Aachen, 52074 Aachen, GermanyInstitute of Clinical Pharmacology, University Hospital of RWTH Aachen, 52074 Aachen, GermanyInstitute of Clinical Pharmacology, University Hospital of RWTH Aachen, 52074 Aachen, GermanyInstitute of Clinical Pharmacology, University Hospital of RWTH Aachen, 52074 Aachen, GermanyBackground: The analysis of substrates of polymorphic cytochrome P450 (CYP) enzymes is important information to enable drug–drug interactions (DDIs) analysis and the relevance of pharmacogenetics in this context in large datasets. Our aim was to compare different approaches to assess the substrate properties of drugs for certain polymorphic CYP2 enzymes. Methods: A standardized manual method and an automatic method were developed and compared to assess the substrate properties for the metabolism of drugs by CYP2D6, 2C9, and 2C19. The automatic method used a matching approach to three freely available resources. We applied the manual and automatic methods to a large real-world dataset deriving from a prospective multicenter study collecting adverse drug reactions in emergency departments in Germany (ADRED). Results: In total, 23,878 medication entries relating to 895 different drugs were analyzed in the real-world dataset. The manual method was able to assess 12.2% (<i>n</i> = 109) of drugs, and the automatic method between 12.1% (<i>n</i> = 109) and 88.9% (<i>n</i> = 796), depending on the resource used. The CYP substrate classifications demonstrated moderate to almost perfect agreements for CYP2D6 and CYP2C19 (Cohen’s Kappa (κ) 0.48–0.90) and fair to moderate agreements for CYP2C9 (κ 0.20–0.48). Conclusion: A closer look at different classifications between methods revealed that both methods are prone to error in different ways. While the automated method excels in time efficiency, completeness, and actuality, the manual method might be better able to identify CYP2 substrates with clinical relevance.https://www.mdpi.com/2227-9059/12/1/161cytochrome P450 enzymeCYP2drug–drug–gene interactiondrug–drug interactionpharmacogeneticspharmacogenomics |
| spellingShingle | Jakob Sommer Justyna Wozniak Judith Schmitt Jana Koch Julia C. Stingl Katja S. Just Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset Biomedicines cytochrome P450 enzyme CYP2 drug–drug–gene interaction drug–drug interaction pharmacogenetics pharmacogenomics |
| title | Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset |
| title_full | Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset |
| title_fullStr | Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset |
| title_full_unstemmed | Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset |
| title_short | Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset |
| title_sort | assessment of substrate status of drugs metabolized by polymorphic cytochrome p450 cyp 2 enzymes an analysis of a large scale dataset |
| topic | cytochrome P450 enzyme CYP2 drug–drug–gene interaction drug–drug interaction pharmacogenetics pharmacogenomics |
| url | https://www.mdpi.com/2227-9059/12/1/161 |
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