Effects of Compound Probiotics on Pharmacokinetics of Cytochrome 450 Probe Drugs in Rats.

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Metabolism and Disposition Pub Date : 2024-10-16 DOI:10.1124/dmd.124.001837
Yanjuan Zhang, Zhi Chen, Yayi Xiao, Tianyuan Wu, Haijun Yang, Yujie Liu, Rong Zhou, Yalan Xiong, Yanling Xiong, Xuechun Yang, Jian Zhou, Honghao Zhou, Wei Zhang, Yan Shu, Xiong Li, Fugang Guo, Jianhui Yin, Shang Liao, Qing Li, Peng Zhu
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Abstract

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450's metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes. SIGNIFICANCE STATEMENT: This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.

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复合益生菌对大鼠体内 CYP450s 探针药物药代动力学的影响。
复合益生菌已被广泛使用,通常与其他药物合用治疗各种慢性疾病,但其对药物药代动力学的影响仍未得到充分探索。本研究阐明了 VSL#3 对细胞色素 P450 酶(CYP450s)探查药物代谢的影响,特别是对奥美拉唑、托布他胺、咪达唑仑、美托洛尔、苯乙酸和氯唑沙宗的影响。给雄性 Wistar 大鼠饮用含有或不含有 VSL#3 的饮用水 14 天,然后在胃内注射 CYP450s 探针鸡尾酒;这样做是为了研究宿主的 CYP450s 代谢表型。采集粪便、肝脏/空肠和血清样本,进行 16S rRNA 测序、RNA 测序和胆汁酸分析。结果表明,益生菌组和药物组大鼠肠道微生物组成的阿尔法和贝塔多样性均存在明显差异。在益生菌组中,奥美拉唑的生物利用度提高了 269.9%,而托布津和氯磺丙脲的生物利用度分别降低了 28.1%和 27.4%。在肝脏和空肠中,两组分别有1,417和4,004个差异表达基因。在益生菌组中,大多数 CYP450s 基因在肝脏中上调,而在空肠中下调。编码代谢酶和药物转运体的基因表达也发生了变化。益生菌组的血清共轭胆汁酸明显减少。益生菌组的十二指肠绒毛变短,回肠绒毛变长。总之,服用 VSL#3 会改变大鼠的肠道微生物群、宿主药物加工基因表达和肠道结构,这可能是导致药代动力学变化的原因。意义声明 本研究主要探讨了益生菌 VSL#3 对 CYP450s 探针药物的药代动力学特征和宿主药物代谢基因表达的影响。与以往的研究相比,本研究结合胆汁酸谱和组织病理学分析,对益生菌改变宿主药物代谢谱进行了全面的解释。
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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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