Effects of CYP2C19 variants on the metabolism of tapentadol in vitro
Objective(s): This study aims to evaluate the catalytic activities of 31 CYP2C19 alleles and their effects on the metabolism of tapentadol in vitro. Materials and Methods: Insect microsomes expressing the CYP2C19 alleles were incubated with 50–1250 μM tapentadol for 40 min at 37 °C and terminated by...
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| Format: | Article |
| Language: | English |
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Mashhad University of Medical Sciences
2022-05-01
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| Series: | Iranian Journal of Basic Medical Sciences |
| Subjects: | |
| Online Access: | https://ijbms.mums.ac.ir/article_20270_79d175a00a5f80ec1bf4a7eb974d8a16.pdf |
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| author | Ren-ai Xu Ping Fang Zhize Ye Mingming Han Jian-Ping Cai Guoxin Hu |
| author_facet | Ren-ai Xu Ping Fang Zhize Ye Mingming Han Jian-Ping Cai Guoxin Hu |
| author_sort | Ren-ai Xu |
| collection | DOAJ |
| description | Objective(s): This study aims to evaluate the catalytic activities of 31 CYP2C19 alleles and their effects on the metabolism of tapentadol in vitro. Materials and Methods: Insect microsomes expressing the CYP2C19 alleles were incubated with 50–1250 μM tapentadol for 40 min at 37 °C and terminated by cooling to -80 °C, immediately. Tapentadol and N-desmethyl tapentadol were analyzed by a UPLC-MS/MS system. The kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl tapentadol were determined. Results: As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered, while CYP2C19.3 and 35FS had no detectable enzyme activity. Only one variant, N277K, showed no significant difference from CYP2C19.1B. Two variants CYP2C19.29 and L16F displayed markedly increased intrinsic clearance values of 302.22% and 199.97%, respectively; whereas 24 variants exhibited significantly decreased relative clearance ranging from 0.32% to 79.15% of CYP2C19.1B. Especially, CYP2C19.2G, 2H, R124Q, and R261W exhibited a drastic decrease in clearance (>80%) compared with wild-type CYP2C19.1B. Conclusion: As the first study of all aforementioned alleles for tapentadol metabolism, the comprehensive data in vitro may provide novel insights into the allele-specific and substrate-specific activity of CYP2C19. |
| first_indexed | 2024-04-12T15:17:08Z |
| format | Article |
| id | doaj.art-1d071226d96f4fcfad5bf473dc120495 |
| institution | Directory Open Access Journal |
| issn | 2008-3866 2008-3874 |
| language | English |
| last_indexed | 2024-04-12T15:17:08Z |
| publishDate | 2022-05-01 |
| publisher | Mashhad University of Medical Sciences |
| record_format | Article |
| series | Iranian Journal of Basic Medical Sciences |
| spelling | doaj.art-1d071226d96f4fcfad5bf473dc1204952022-12-22T03:27:35ZengMashhad University of Medical SciencesIranian Journal of Basic Medical Sciences2008-38662008-38742022-05-0125565966310.22038/ijbms.2022.56996.1271020270Effects of CYP2C19 variants on the metabolism of tapentadol in vitroRen-ai Xu0Ping Fang1Zhize Ye2Mingming Han3Jian-Ping Cai4Guoxin Hu5The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaThe First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSchool of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaSchool of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaThe Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, ChinaSchool of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaObjective(s): This study aims to evaluate the catalytic activities of 31 CYP2C19 alleles and their effects on the metabolism of tapentadol in vitro. Materials and Methods: Insect microsomes expressing the CYP2C19 alleles were incubated with 50–1250 μM tapentadol for 40 min at 37 °C and terminated by cooling to -80 °C, immediately. Tapentadol and N-desmethyl tapentadol were analyzed by a UPLC-MS/MS system. The kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl tapentadol were determined. Results: As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered, while CYP2C19.3 and 35FS had no detectable enzyme activity. Only one variant, N277K, showed no significant difference from CYP2C19.1B. Two variants CYP2C19.29 and L16F displayed markedly increased intrinsic clearance values of 302.22% and 199.97%, respectively; whereas 24 variants exhibited significantly decreased relative clearance ranging from 0.32% to 79.15% of CYP2C19.1B. Especially, CYP2C19.2G, 2H, R124Q, and R261W exhibited a drastic decrease in clearance (>80%) compared with wild-type CYP2C19.1B. Conclusion: As the first study of all aforementioned alleles for tapentadol metabolism, the comprehensive data in vitro may provide novel insights into the allele-specific and substrate-specific activity of CYP2C19.https://ijbms.mums.ac.ir/article_20270_79d175a00a5f80ec1bf4a7eb974d8a16.pdfcytochrome p450cyp2c19 variantsdrug metabolismgenetic polymorphismtapentadol |
| spellingShingle | Ren-ai Xu Ping Fang Zhize Ye Mingming Han Jian-Ping Cai Guoxin Hu Effects of CYP2C19 variants on the metabolism of tapentadol in vitro Iranian Journal of Basic Medical Sciences cytochrome p450 cyp2c19 variants drug metabolism genetic polymorphism tapentadol |
| title | Effects of CYP2C19 variants on the metabolism of tapentadol in vitro |
| title_full | Effects of CYP2C19 variants on the metabolism of tapentadol in vitro |
| title_fullStr | Effects of CYP2C19 variants on the metabolism of tapentadol in vitro |
| title_full_unstemmed | Effects of CYP2C19 variants on the metabolism of tapentadol in vitro |
| title_short | Effects of CYP2C19 variants on the metabolism of tapentadol in vitro |
| title_sort | effects of cyp2c19 variants on the metabolism of tapentadol in vitro |
| topic | cytochrome p450 cyp2c19 variants drug metabolism genetic polymorphism tapentadol |
| url | https://ijbms.mums.ac.ir/article_20270_79d175a00a5f80ec1bf4a7eb974d8a16.pdf |
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