The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone
The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 var...
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| Format: | Article |
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Elsevier
2023-12-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223016311 |
| _version_ | 1797630629688377344 |
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| author | Qingqing Li Jing Wang Zheng-lu Wang Yuxin Shen Qi Zhou Ya-nan Liu Guo-xin Hu Jian-ping Cai Ren-ai Xu |
| author_facet | Qingqing Li Jing Wang Zheng-lu Wang Yuxin Shen Qi Zhou Ya-nan Liu Guo-xin Hu Jian-ping Cai Ren-ai Xu |
| author_sort | Qingqing Li |
| collection | DOAJ |
| description | The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti–tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague–Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra–performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID–14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC50 were 18.83 ± 1.06 μM and 16.15 ± 0.81 μM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC(0−t) and AUC(0-∞) of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CLz/F was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone. |
| first_indexed | 2024-03-11T11:10:52Z |
| format | Article |
| id | doaj.art-b8b5f4b3151a4e42977a3e12672a24d6 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T11:10:52Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-b8b5f4b3151a4e42977a3e12672a24d62023-11-12T04:39:29ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-12-01168115833The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidoneQingqing Li0Jing Wang1Zheng-lu Wang2Yuxin Shen3Qi Zhou4Ya-nan Liu5Guo-xin Hu6Jian-ping Cai7Ren-ai Xu8The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaInstitute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaInstitute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Corresponding authors.The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; The 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, China; Corresponding author at: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Corresponding authors.The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti–tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague–Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra–performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID–14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC50 were 18.83 ± 1.06 μM and 16.15 ± 0.81 μM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC(0−t) and AUC(0-∞) of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CLz/F was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.http://www.sciencedirect.com/science/article/pii/S0753332223016311LurasidoneCYP3A4 genetic polymorphismOlmutinibInteraction |
| spellingShingle | Qingqing Li Jing Wang Zheng-lu Wang Yuxin Shen Qi Zhou Ya-nan Liu Guo-xin Hu Jian-ping Cai Ren-ai Xu The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone Biomedicine & Pharmacotherapy Lurasidone CYP3A4 genetic polymorphism Olmutinib Interaction |
| title | The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone |
| title_full | The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone |
| title_fullStr | The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone |
| title_full_unstemmed | The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone |
| title_short | The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone |
| title_sort | impacts of cyp3a4 genetic polymorphism and drug interactions on the metabolism of lurasidone |
| topic | Lurasidone CYP3A4 genetic polymorphism Olmutinib Interaction |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223016311 |
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