Gut Microbiota-Regulated Pharmacokinetics of Berberine and Active Metabolites in Beagle Dogs After Oral Administration.
Gut Microbiota-Regulated Pharmacokinetics of Berberine and Active Metabolites in Beagle Dogs After Oral Administration.
复制标题
DOI：
10.3389/fphar.2018.00214
复制
发表时间：
2018
影响因子：
5.6
通讯作者：
Jiang JD
中科院分区：
文献类型：
--
作者：
Feng R;Zhao ZX;Ma SR;Guo F;Wang Y;Jiang JD
小檗碱（BBR）被认为是一种具有显著优势的多靶点药物。与临床药理作用显著相反，血中BBR含量很低。我们之前的工作表明，二氢小檗碱（dhBBR）可能是BBR在肠道中的一种可吸收形式，丁酸盐是大鼠肠道细菌产生的一种活性代谢物。在这项研究中，我们首次描述了口服BBR单剂量（50 mg/kg）或多剂量（50 mg/kg/d） 7天后比格犬肠道微生物调节的药代动力学。采用GC-MS、GC、LC-MS/MS和LC/MS - it - tof分别检测dhBBR、丁酸酯和BBR及其I期和II期代谢产物。结果显示，犬血浆中未检测到dhBBR，但在第3天和第7天检查犬的粪便中有少量排泄。丁酸盐由肠道细菌产生，与治疗前相比，BBR处理7天后血浆和粪便中的丁酸盐分别增加了1.3倍和1.2倍。采用16S rRNA基因分析分析肠道细菌组成的变化。结果表明，接受BBR治疗7天的狗增加了产生丁酸盐和硝基还原酶的细菌的丰度。我们还鉴定了第一阶段和第二阶段代谢物的化学结构，并分析了它们在比格犬中的含量。口服BBR （50 mg/kg）后，在狗的血浆和粪便中检测到11种代谢物，其中包括8种I期代谢物和8种II期代谢物。药动学分析显示血浆中BBR浓度较低，Cmax值为36.88±23.45 ng/mL。血浆中葡萄糖醛酸偶联物（M11）的相对含量高于其他代谢物（M1、M2、M12和M14）。粪便中检测到BBR，第3天高排泄量（2625.04±1726.94 μg），第7天高排泄量（2793.43±488.10 μg/g）。综上所述，本研究首次描述了口服BBR后beagle犬肠道菌群调节的药代动力学，有助于发现吸收差但疗效好的药物。
Berberine (BBR) is considered a multi-target drug that has significant advantages. In contrast to its significant pharmacological effects in clinic, the plasma level of BBR is very low. Our previous work revealed that dihydroberberine (dhBBR) could be an absorbable form of BBR in the intestine, and butyrate is an active metabolite that is generated by gut bacteria in rats. In this study, for the first time we describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR by single (50 mg/kg) or multiple doses (50 mg/kg/d) for 7 days. GC-MS, GC, LC-MS/MS, and LC/MSn-IT-TOF were used to detect dhBBR, butyrate and BBR as well as its Phase I and II metabolites, respectively. The results showed that dhBBR was not detected in dog plasma but was excreted in small amounts in the feces of dogs examined on days 3 and 7. Butyrate was generated by gut bacteria and increased by 1.3- and 1.2-fold in plasma or feces, respectively, after 7 days of BBR treatment compared to the levels before treatment. Changes of intestinal bacterial composition were analyzed by 16S rRNA genes analysis. The results presented that dogs treated with BBR for 7 days increased both the abundance of the butyrate- and the nitroreductases- producing bacteria. We also identified chemical structures of the Phase I and II metabolites and analyzed their contents in beagle dogs. Eleven metabolites were detected in plasma and feces after BBR oral administration (50 mg/kg) to dogs, including 8 metabolites of Phase I and III metabolites of Phase II. The pharmacokinetic profile indicated that the concentration of BBR in plasma was low, with a Cmax value of 36.88 ± 23.45 ng/mL. The relative content of glucuronic acid conjugates (M11) was higher than those of other metabolites (M1, M2, M12, and M14) in plasma. BBR was detected in feces, with high excreted amounts on day 3 (2625.04 ± 1726.94 μg/g) and day 7 (2793.43 ± 488.10 μg/g). In summary, this is the first study to describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR, which is beneficial for discovery of drugs with poor absorption but good therapeutic efficacy.
登录
查看更多内容
CYP450同工酶转化小檗碱代谢物的生物活性
影响因子：
7.4
作者：
Li Y;Ren G;Wang YX;Kong WJ;Yang P;Wang YM;Li YH;Yi H;Li ZR;Song DQ;Jiang JD
通讯作者：
Jiang JD
影响因子：
9.4
作者：
Schapiro, JM;Gupta, R;Limaye, AP
通讯作者：
Limaye, AP
影响因子：
3.7
作者：
Tan XS;Ma JY;Feng R;Ma C;Chen WJ;Sun YP;Fu J;Huang M;He CY;Shou JW;He WY;Wang Y;Jiang JD
通讯作者：
Jiang JD
DOI：
10.1038/ijo.2015.84
发表时间：
2015-09
期刊：
International journal of obesity (2005)
影响因子：
--
作者：
Byrne CS;Chambers ES;Morrison DJ;Frost G
通讯作者：
Frost G
影响因子：
2.6
作者：
Sandri, Misa;Dal Monego, Simeone;Stefanon, Bruno
通讯作者：
Stefanon, Bruno