Department of Pharmacy, Shaoxing Second Hospital, Shaoxing, Zhejiang, China.
Department of Pharmacy, Shaoxing Keqiao Women & Children΄s Hospital, Shaoxing, Zhejiang, China.
Toxicol Appl Pharmacol. 2023 Sep 15;475:116653. doi: 10.1016/j.taap.2023.116653. Epub 2023 Aug 14.
Ibuprofen is the most commonly used analgesic. CYP polymorphisms are mainly responsible for the differences in drug metabolism among individuals. Variations in the ability of populations to metabolize ibuprofen can lead to drug exposure events. The aim of this study was to evaluate the effects of CYP2C19 and CYP3A4 polymorphisms on ibuprofen metabolism in a Chinese population.
First, 31 CYP2C19 and 12 CYP3A4 microsomal enzymes were identified using an insect expression system. Then, variants were evaluated using a mature incubation system. Moreover, ibuprofen metabolite content was determined via ultra-performance liquid chromatography-tandem mass spectrometry analysis. Finally, kinetic parameters of CYP2C19 and CYP3A4 genotypes were determined via Michaelis-Menten curve fitting.
Most variants exhibited significantly altered intrinsic clearance compared to the wild type. In the CYP2C19 metabolic pathway, seven variants exhibited no significant alterations in intrinsic clearance (CL), six variants exhibited significantly high CL (121-291%), and the remaining 15 variants exhibited substantially reduced CL (1-71%). In the CYP3A4 metabolic pathway, CYP3A4*30 was not detected in the metabolite content due to the absence of activity, and 10 variants exhibited significantly reduced CL.
To the best of our knowledge, this is the first study to assess the kinetic characteristics of 31 CYP2C19 and 12 CYP3A4 genotypes on ibuprofen metabolism. However, further studies are needed on poor metabolizers as they are more susceptible to drug exposure. Our findings suggest that the kinetic characteristics in combination with artificial intelligence to predict the toxicity of ibuprofen and reduce any adverse drug reactions.
布洛芬是最常用的镇痛药。CYP 多态性主要负责个体间药物代谢的差异。人群代谢布洛芬能力的变化可导致药物暴露事件。本研究旨在评估 CYP2C19 和 CYP3A4 多态性对中国人群中布洛芬代谢的影响。
首先，使用昆虫表达系统鉴定了 31 种 CYP2C19 和 12 种 CYP3A4 微粒体酶。然后，使用成熟的孵育系统评估变体。此外，通过超高效液相色谱-串联质谱分析测定布洛芬代谢物含量。最后，通过米氏方程拟合测定 CYP2C19 和 CYP3A4 基因型的动力学参数。
与野生型相比，大多数变体的固有清除率明显改变。在 CYP2C19 代谢途径中，七种变体的固有清除率（CL）没有明显变化，六种变体的 CL 显著升高（121-291%），其余 15 种变体的 CL 明显降低（1-71%）。在 CYP3A4 代谢途径中，由于缺乏活性，CYP3A4*30 在代谢物含量中未被检测到，10 种变体的 CL 明显降低。
据我们所知，这是第一项评估 31 种 CYP2C19 和 12 种 CYP3A4 基因型对布洛芬代谢的动力学特征的研究。然而，需要对代谢不良者进行进一步研究，因为他们更容易受到药物暴露的影响。我们的研究结果表明，动力学特征与人工智能相结合，可以预测布洛芬的毒性，减少任何不良反应。
