复方益生菌对大鼠细胞色素 450 探针药物药代动力学的影响。
Effects of Compound Probiotics on Pharmacokinetics of Cytochrome 450 Probe Drugs in Rats.
机构信息
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.).
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); National Clinical Research Center for Geriatric Disorders, Changsha, China (Y.Z., Y.X., T.W., H.Y., Y.L., R.Z., Yal.X., Yan.X., X.Y., J.Z., H.Z., W.Z., Q.L., P.Z.); Department of Hypertension, Xingsha Hospital, Changsha, China (Z.C., F.G., J.Y., S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)
出版信息
Drug Metab Dispos. 2024 Oct 16;52(11):1297-1312. doi: 10.1124/dmd.124.001837.
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 and 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.
复合益生菌已被广泛应用，并常与其他药物联合用于治疗各种慢性疾病，但它们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（P450s）探针药物代谢的影响，特别是奥美拉唑、甲苯磺丁脲、咪达唑仑、美托洛尔、非那西汀和氯唑沙宗。雄性 Wistar 大鼠连续 14 天饮用含或不含 VSL#3 的水，然后胃内给予 P450 探针混合物；这是为了研究宿主 P450 的代谢表型。收集粪便、肝/空肠和血清样本进行 16S 核糖体 RNA 测序、RNA 测序和胆汁酸谱分析。结果表明，益生菌组和载体组大鼠肠道微生物组成的 和 多样性存在显著差异。在益生菌组中，奥美拉唑的生物利用度增加了 269.9%，而甲苯磺丁脲和氯磺丙脲的生物利用度分别降低了 28.1%和 27.4%。两组肝和空肠分别有 1417 和 4004 个差异表达基因。在益生菌组中，大多数 P450 基因在肝脏中上调，但在空肠中下调。代谢酶和药物转运蛋白的基因表达也发生了变化。益生菌组血清结合胆汁酸显著减少。在益生菌组中发现十二指肠绒毛变短，回肠绒毛变长。总之，VSL#3 给药改变了大鼠的肠道微生物群、宿主药物处理基因表达和肠道结构，这可能是药代动力学变化的原因。
意义陈述
本研究重点研究了益生菌 VSL#3 对细胞色素 P450 探针药物药代动力学特征和宿主药物代谢基因表达的影响。与以前的研究相比，本研究结合胆汁酸谱和组织病理学分析，为益生菌修饰的宿主药物代谢谱提供了全面的解释。
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