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Study on genotype and phenotype of novel CYP2D6 variants using pharmacokinetic and pharmacodynamic models with metoprolol as a substrate drug

The Pharmacogenomics Journal volume 24, Article number: 13 (2024) Cite this article

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Abstract

To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug.

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Fig. 1: The pharmacokinetic profile of metoprolol in plasma and urine.
Fig. 2: Correlation of metoprolol blood concentration with systolic blood pressure.
Fig. 3: Correlation of metoprolol blood concentration with P-R prolongation.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81973397), the Natural Science Foundation of Zhejiang Province (LTGC23H310001), and the National Key Research and Development Program of China (2020YFC2008301).

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Authors and Affiliations

  1. Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Jianchang Qian, Tao Xu, Guoxin Hu & Jianping Cai

  2. Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China

    Peipei Pan

  3. Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Wei Sun

  4. The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, 100005, China

    Jianping Cai

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  1. Jianchang Qian
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Jianchang Qian and Tao Xu wrote the main manuscript text. Tao Xu, Peipei Pan and Wei Sun conducted the experiment, analysis the results, and prepared the figures/tables. Jianping Cai and Guoxin Hu designed the experiment. All authors reviewed the manuscript.

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Correspondence to Jianchang Qian, Guoxin Hu or Jianping Cai.

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Qian, J., Xu, T., Pan, P. et al. Study on genotype and phenotype of novel CYP2D6 variants using pharmacokinetic and pharmacodynamic models with metoprolol as a substrate drug. Pharmacogenomics J 24, 13 (2024). https://doi.org/10.1038/s41397-024-00332-3

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