Effect of Gut Microbiota on the Pharmacokinetics of Nifedipine in Spontaneously Hypertensive Rats.
Effect of Gut Microbiota on the Pharmacokinetics of Nifedipine in Spontaneously Hypertensive Rats.
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肠道微生物区系对硝苯地平在自发性高血压大鼠体内药代动力学的影响
DOI：
10.3390/pharmaceutics15082085
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发表时间：
2023-08-03
期刊：
影响因子：
5.4
通讯作者：
Li, Qing
中科院分区：
文献类型：
--
作者：
Zhou, Rong;Yang, Haijun;Zhu, Peng;Liu, Yujie;Zhang, Yanjuan;Zhang, Wei;Zhou, Honghao;Li, Xiong;Li, Qing
临床上广泛观察到的硝苯地平的药代动力学变异性不能完全用药物基因组学来解释。作为影响药物代谢的一个新因素，肠道菌群如何影响硝苯地平的药代动力学需要进一步探讨。以常用于高血压相关研究的自发性高血压大鼠（Sponsoringhypertensive rats，SHR）为实验组，Wistar大鼠为对照组。本研究中，硝苯地平在SHR体内的生物利用度较Wistar大鼠降低了18.62%（P < 0.05）。微生物群的变化与药代动力学的差异有关。多氏拟杆菌的相对丰度与AUC 0-t（r = −0.881，p = 0.004）和Cmax（r = −0.714，p = 0.047）呈负相关。血清胆汁酸（BA）谱分析表明，甘氨熊去氧胆酸（GUDCA）和甘氨鹅去氧胆酸（GCDCA）显着增加的SHR。与Wistar大鼠相比，SHR大鼠的CYP 3A 1和PXR表达上调，CYP 3A 1酶活性升高。斯皮尔曼等级相关显示粪拟杆菌与GUDCA（r =-0.7126，p = 0.0264）和GCDCA（r =-0.6878，p = 0.0339）呈负相关。此外，GUDCA与Cmax呈负相关（r =-0.556，p = 0.025）。在原代大鼠肝细胞中，GUDCA可诱导PXR靶基因CYP 3A 1和Mdr 1a的表达。此外，SHR的抗生素治疗证实了微生物群对硝苯地平药代动力学的影响。通常，肠道微生物群通过微生物生物转化或通过调节CYP 3A 1的酶活性来影响硝苯地平的药代动力学。
The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly used in hypertension-related research and served as the experimental groups; Wistar rats were used as control groups. In this study, the bioavailability of nifedipine decreased by 18.62% (p < 0.05) in the SHRs compared with the Wistar rats. Changes in microbiota were associated with the difference in pharmacokinetics. The relative abundance of Bacteroides dorei was negatively correlated with AUC0–t (r = −0.881, p = 0.004) and Cmax (r = −0.714, p = 0.047). Analysis of serum bile acid (BA) profiles indicated that glycoursodeoxycholic acid (GUDCA) and glycochenodeoxycholic acid (GCDCA) were significantly increased in the SHRs. Compared with the Wistar rats, the expressions of CYP3A1 and PXR were upregulated and the enzyme activity of CYP3A1 increased in the SHRs. Spearman’s rank correlation revealed that Bacteroides stercoris was negatively correlated with GUDCA (r = −0.7126, p = 0.0264) and GCDCA (r = −0.6878, p = 0.0339). Moreover, GUDCA was negatively correlated with Cmax (r = −0.556, p = 0.025). In primary rat hepatocytes, GUDCA could induce the expressions of PXR target genes CYP3A1 and Mdr1a. Furthermore, antibiotic treatments in SHRs verified the impact of microbiota on the pharmacokinetics of nifedipine. Generally, gut microbiota affects the pharmacokinetics of nifedipine through microbial biotransformation or by regulating the enzyme activity of CYP3A1.
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