Xiong Yalan, Xiong Yanling, Yang Haijun, Guo Fugang, Yin Jianhui, Liao Shang, Chen Zhi, Zhang Wei, Zhou Honghao, Weng Chunyan, Li Qing
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China; National Clinical Research Center for Geriatric Disorders, Changsha, China.
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Department of Pharmacy, The First Hospital of Nanchang, The Third Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China; National Clinical Research Center for Geriatric Disorders, Changsha, China.
Drug Metab Dispos. 2025 Jun 27;53(8):100116. doi: 10.1016/j.dmd.2025.100116.
Despite nifedipine's satisfactory efficacy, patients with higher blood pressure often require combination therapy or increased dosages. The reasons for the reduced efficacy of nifedipine in this population remain unclear. Here, this study aimed to explore whether there are differences in nifedipine pharmacokinetics among rats with different blood pressure level and to assess the role of gut microbiota in this process. Spontaneously hypertensive rats (SHR) at 8, 12, and 16 weeks and age-matched Wistar-Kyoto (WKY) rats were used to study the pharmacokinetics of nifedipine. The WKY rats were used as the control group. We examined the pharmacokinetics of nifedipine in both SHR and WKY rats of different ages, analyzing the composition of gut microbiota and the bile acids profile in these age groups. The area under the concentration-time curve and C of nifedipine in SHR decreased progressively with age. Compared with 8-week-old SHR, the expression of CYP3A1 in the liver was significantly upregulated in both 12-week-old and 16-week-old SHR. Five bacterial genera potentially related to the pharmacokinetics of nifedipine were identified: Romboutsia, the Lachnospiraceae_NK4A136_group, Alistipes, Anaerostipes, and Ruminococcaceae_UCG-013. We found that 8 bile acids, including cholic acid, ursodeoxycholic acid, glycocholic acid, taurolithocholic acid, glycolithocholic acid, glycoursodeoxycholic acid, glycochenodeoxycholic acid, and tauro-β-muricholic acid, were reduced with increasing age in SHR. In conclusion, our results suggest that there are significant differences in nifedipine pharmacokinetics among SHR of different blood pressure. The increasing expression of CYP3A1 in the liver and direct metabolism of gut microbiota were likely the main reasons. SIGNIFICANCE STATEMENT: This study explores blood pressure-dependent differences in nifedipine pharmacokinetics in spontaneously hypertensive rats and reveals the roles of liver enzyme expression and gut microbiota metabolism in the process. Understanding these factors is crucial for addressing disease-related variability in drug efficacy and resistance, offering insights that could enhance personalized treatment strategies for hypertension and other associated diseases.
尽管硝苯地平疗效令人满意，但血压较高的患者通常需要联合治疗或增加剂量。硝苯地平在该人群中疗效降低的原因尚不清楚。在此，本研究旨在探讨不同血压水平的大鼠之间硝苯地平药代动力学是否存在差异，并评估肠道微生物群在此过程中的作用。使用8周、12周和16周龄的自发性高血压大鼠（SHR）以及年龄匹配的Wistar-Kyoto（WKY）大鼠来研究硝苯地平的药代动力学。WKY大鼠用作对照组。我们检测了不同年龄的SHR和WKY大鼠中硝苯地平的药代动力学，分析了这些年龄组中肠道微生物群的组成和胆汁酸谱。SHR中硝苯地平的浓度-时间曲线下面积和C随年龄逐渐降低。与8周龄的SHR相比，12周龄和16周龄的SHR肝脏中CYP3A1的表达均显著上调。鉴定出五个可能与硝苯地平药代动力学相关的细菌属：罗姆布茨菌属、毛螺菌科_NK4A136_组、阿利斯杆菌属、厌氧棒菌属和瘤胃球菌科_UCG-013。我们发现，包括胆酸、熊去氧胆酸、甘氨胆酸、牛磺石胆酸、甘氨石胆酸、甘氨熊去氧胆酸、甘氨鹅去氧胆酸和牛磺-β-鼠胆酸在内的8种胆汁酸在SHR中随年龄增加而减少。总之，我们的结果表明不同血压的SHR之间硝苯地平药代动力学存在显著差异。肝脏中CYP3A1表达的增加和肠道微生物群的直接代谢可能是主要原因。意义声明：本研究探讨了自发性高血压大鼠中硝苯地平药代动力学的血压依赖性差异，并揭示了肝酶表达和肠道微生物群代谢在此过程中的作用。了解这些因素对于解决疾病相关的药物疗效和耐药性变异性至关重要，为改善高血压及其他相关疾病的个性化治疗策略提供了见解。
