药学学报

Typical drug	Clinical use	Influence on drugs	Pharmacological/toxicological consequence	Related bacteria/ enzyme	Ref.
Sulfasalazine	Sulfonamides	Metabolism↑	Toxicity↑ (prodrug activation to sulfapyridine and 5-aminosalicylic acid)	Azoreductase Enzymes	^[43]
Prontosil	Sulfonamides	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[53]
Olsalazine	Treatment of ulcerative colitis	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[54]
Balsalazide	Treatment of ulcerative colitis	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[55]
Lovastatin	Antihyperlipidemic drugs	Metabolism↑	Activity↑ (prodrug activation as active hydroxy acid metabolite)	Not reported	^[45]
Simvastatin	Antihyperlipidemic drugs	Metabolism↑	Activity↑	Lactobacillus	^[56]
Amiodarone	Antiarrhythmic drugs	AUC↑ Absorption↑	Activity↑	Escherichia coli Nissle 1917	^[46]
Digoxin	Anti-chronic cardiac insufficiency	Metabolism↑ (reduction reaction)	Cardiotonic effect↑	Eggerthella lenta	^[57]
Irinotecan	Treatment of colorectal cancer	Metabolism↑ Slow excretion	Toxicity↑ (SN-38 activity activated)	Escherichia coli, Bacteroides vulgatus and Clostridium ramosum, β-Glucuronidase enzymes	^[50]
Indomethacin	Anti-inflammatory analgesics	Metabolism↑ Slow excretion	Toxicity↑ (enterohepatic circulation)	β-Glucuronidase enzymes	^[58]
Acetaminophen	Antipyretic analgesics	Metabolism↓	Liver toxicity↑	Clostridium difficile	^[52]
Insulin	Hypoglycemic drugs	Metabolism↑	Activity↓ Blood sugar↓	Protease	^[59]
Levodopa	Anti-Parkinson's disease	Absorption↓ Metabolism↑	Activity↓	Helicobacter pylori	^[60]
Metronidazole	Anti-amoebiasis	AUC↓	Activity↓	Clostridium perfringens	^[61]
Nitrazepam	Benzodiazepine sedative hypnotics	Metabolism↑	Toxicity↑ (teratogenicity)	Nitroreductase Enzymes	^[62]
Chloramphenicol	Bacteriostatic broad- spectrum antibiotics	Metabolism↑	Toxicity↑	Not reported	^[63]
Nizatidine	Gastric acid secretion inhibitor	Metabolism↑	Activity↓	Not reported	^[64]
Ranitidine	Gastric acid secretion inhibitor	Metabolism↑	Activity↓	Not reported	^[65]
Risperidone	Antipsychotics	Metabolism↑	Activity↓	Not reported	^[66]
Amlodipine	Antihypertensive drugs	C_max↑AUC↑	Activity↑	Not reported	^[67]
Nifedipine	Antihypertensive drugs	AUC↑ Slow excretion	Activity↑	Not reported	^[27]
Levamisole	Intestinal repellent	Metabolism↓	Activity↑	Bacteroides, Clostridium species	^[68]

Typical drug	Clinical use	Influence on drugs	Pharmacological/toxicological consequence	Related bacteria/ enzyme	Ref.
Sulfasalazine	Sulfonamides	Metabolism↑	Toxicity↑ (prodrug activation to sulfapyridine and 5-aminosalicylic acid)	Azoreductase Enzymes	^[43]
Prontosil	Sulfonamides	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[53]
Olsalazine	Treatment of ulcerative colitis	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[54]
Balsalazide	Treatment of ulcerative colitis	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[55]
Lovastatin	Antihyperlipidemic drugs	Metabolism↑	Activity↑ (prodrug activation as active hydroxy acid metabolite)	Not reported	^[45]
Simvastatin	Antihyperlipidemic drugs	Metabolism↑	Activity↑	Lactobacillus	^[56]
Amiodarone	Antiarrhythmic drugs	AUC↑ Absorption↑	Activity↑	Escherichia coli Nissle 1917	^[46]
Digoxin	Anti-chronic cardiac insufficiency	Metabolism↑ (reduction reaction)	Cardiotonic effect↑	Eggerthella lenta	^[57]
Irinotecan	Treatment of colorectal cancer	Metabolism↑ Slow excretion	Toxicity↑ (SN-38 activity activated)	Escherichia coli, Bacteroides vulgatus and Clostridium ramosum, β-Glucuronidase enzymes	^[50]
Indomethacin	Anti-inflammatory analgesics	Metabolism↑ Slow excretion	Toxicity↑ (enterohepatic circulation)	β-Glucuronidase enzymes	^[58]
Acetaminophen	Antipyretic analgesics	Metabolism↓	Liver toxicity↑	Clostridium difficile	^[52]
Insulin	Hypoglycemic drugs	Metabolism↑	Activity↓ Blood sugar↓	Protease	^[59]
Levodopa	Anti-Parkinson's disease	Absorption↓ Metabolism↑	Activity↓	Helicobacter pylori	^[60]
Metronidazole	Anti-amoebiasis	AUC↓	Activity↓	Clostridium perfringens	^[61]
Nitrazepam	Benzodiazepine sedative hypnotics	Metabolism↑	Toxicity↑ (teratogenicity)	Nitroreductase Enzymes	^[62]
Chloramphenicol	Bacteriostatic broad- spectrum antibiotics	Metabolism↑	Toxicity↑	Not reported	^[63]
Nizatidine	Gastric acid secretion inhibitor	Metabolism↑	Activity↓	Not reported	^[64]
Ranitidine	Gastric acid secretion inhibitor	Metabolism↑	Activity↓	Not reported	^[65]
Risperidone	Antipsychotics	Metabolism↑	Activity↓	Not reported	^[66]
Amlodipine	Antihypertensive drugs	C_max↑AUC↑	Activity↑	Not reported	^[67]
Nifedipine	Antihypertensive drugs	AUC↑ Slow excretion	Activity↑	Not reported	^[27]
Levamisole	Intestinal repellent	Metabolism↓	Activity↑	Bacteroides, Clostridium species	^[68]

药物微生物组学研究进展

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孙月梅 ¹ , 张雅婷 ² , 张娟红 ¹ , 李雪 ² , 王荣 ¹^,²^,^* , 李文斌 ¹^,^*

药学学报 | 综述 2020,55(10): 2314-2321

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药学学报 | 综述 2020, 55(10): 2314-2321

药物微生物组学研究进展

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孙月梅¹, 张雅婷², 张娟红¹, 李雪², 王荣¹^,²^,^*, 李文斌¹^,^*

作者信息

1.中国人民解放军联勤保障部队第九四〇医院, 全军高原医学重点实验室, 甘肃兰州 730050

2.兰州大学药学院, 甘肃兰州 730000

通讯作者:

*王荣,Tel: 86-931-8994675, E-mail: wangrong-69@163.com;

李文斌,Tel: 86-931-8994675, E-mail: yfcs2002@163.com

Advances in the study of gut pharmacomicrobiomics

Yue-mei SUN¹, Ya-ting ZHANG², Juan-hong ZHANG¹, Xue LI², Rong WANG¹^,²^,^*, Wen-bin LI¹^,^*

Affiliations

1. Key Laboratory for Prevention and Remediation of Plateau Environmental Damage, the 940 th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, China

2. College of Pharmacy, Lanzhou University, Lanzhou 730000, China

出版时间: 2020-10-12 doi: 10.16438/j.0513-4870.2020-0455

文章导航

摘要

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肠道菌群是寄居在人类和动物消化道中多样化和系统化的微生物群落，其难以预测的结构修饰很大程度上可以改变药物在体内的药物代谢动力学，从而进一步影响药物的临床疗效。本文从前药活化、药物失活、产生毒性等三方面综述了肠道菌群介导的药物代谢、高原缺氧环境对肠道菌群的组成和数量的影响以及对药物代谢的影响。研究和阐明肠道菌群对药物代谢的影响，不仅有利于个体化用药，也有利于合理设计药物，最终将更好地预测和理解个体药物反应以及调节肠道微生物组来提高药物药效，从而促进个性化医疗。

关键词

肠道菌群 / 药物代谢动力学 / 疗效 / 高原缺氧 / 个体化用药

Abstract

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The intestinal flora is a diverse microbial community living in the digestive tract of humans and animals. This microbial community can modify drugs in unpredictable ways, leading to changes in the pharmacokinetics of drugs in vivo and affecting their clinical efficacy. Here we review drug metabolism mediated by intestinal flora from three aspects:prodrug activation, drug inactivation, and toxicity. The effect of the stable hypoxic environment on the composition and quantity of intestinal flora and the effect on drug metabolism are discussed. Understanding the influence of intestinal flora on drug metabolism is not only conducive to individualized medication, but also conducive to rational drug design, allowing us to predict and understand individual drug response and regulate the intestinal microbiome to improve drug efficacy, thus promoting personalized medicine.

Key words

intestinal flora / pharmacokinetics / efficacy / plateau hypoxic environment / individualized medication

引用本文

孙月梅, 张雅婷, 张娟红, 李雪, 王荣, 李文斌. 药物微生物组学研究进展. 药学学报, 2020 , 55 (10) : 2314 -2321 . DOI: 10.16438/j.0513-4870.2020-0455

Yue-mei SUN, Ya-ting ZHANG, Juan-hong ZHANG, Xue LI, Rong WANG, Wen-bin LI. Advances in the study of gut pharmacomicrobiomics[J]. Acta Pharmaceutica Sinica, 2020 , 55 (10) : 2314 -2321 . DOI: 10.16438/j.0513-4870.2020-0455

正文

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肠道微生物群是栖息在哺乳动物胃肠道中的大家族, 不仅可以维系机体健康, 也可以代谢外源性物质, 其代谢药物的能力与身体任何器官相当, 包括代谢药物的主要器官肝脏^[1]。药物微生物组学可用来表示肠道微生物群变化对药物药代动力学和药效学的影响^[2]。为了确保口服药物在胃肠道的安全性和稳定性, 将药物进行制剂改良, 如制成肠溶衣、缓控释、低溶解度/低渗透性等特征的现代药物剂型, 上述特点使药物在胃肠道中停留时间延长, 从而也有利于共生细菌对药物进行生物转化^[3]。本文主要综述肠道菌群对药物代谢的影响, 以及高原环境下肠道菌群在药物代谢动力学变化中的重要地位。

1 肠道菌群的组成

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肠道菌群是极其多样化的微生物群落。截至目前, 16S rRNA焦磷酸测序研究显示人类胃肠道微生物群包含两千多个物种。大多数物种属于8个门:厚壁菌门、拟杆菌门、变形菌门、放线菌门、梭杆菌门、疣孢菌门、蓝细菌门和螺旋体门, 其中, 80%以上的物种属于厚壁菌门和拟杆菌门^{[4, 5]}。大部分研究表明人体胃肠道在胎儿期是无菌的, 在出生期间和出生后不久, 由生产方式决定体内微生物群落。阴道分娩的婴儿由母体阴道和粪便定植, 主要有乳酸杆菌、纤毛菌、普氏菌等。通过剖腹产分娩的婴儿, 主要有金葡菌、棒状杆菌、丙酸杆菌等^{[6, 7]}。成年期, 人类的肠道微生物基本稳定。衰老时期, 核心微生物群与成年期差异较大, 其中, 拟杆菌的比例更高^[8]。

2 影响肠道菌群组成的因素

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肠道微生物群是地球上复杂的生态系统之一, 其与宿主之间的相互作用导致了其组成和功能的多样性。肠道微生物群的组成失衡可导致短暂的肠功能障碍或病理性状态^{[9, 10]}。已经发现许多因素影响微生物群的组成, 包括昼夜节律、抗生素和益生菌的使用以及环境影响等^{[11, 12]}。

2.1 昼夜节律对肠道菌群的影响

昼夜节律是生物体的行为以24 h左右为周期的模式波动, 使其生物功能与环境模式相一致来维持机体健康^[13]。内源性昼夜节律条件下饮食、进食时间和其他因素都会导致微生物群落结构和微生物活性的改变。反过来, 微生物的代谢活动, 部分通过产生短链脂肪酸, 这是哺乳动物免疫和代谢功能的关键调节剂, 进而对宿主的免疫和代谢功能产生显著影响^[14]。Thaiss等^[15]研究表明高达20%的肠道细菌相对丰度和活性存在昼夜波动, 而且雌性小鼠的细菌节律波动比雄性小鼠更显著^[16]。昼夜节律紊乱或者分子时钟的遗传扰动都会导致肠道微生物群落的生物失调, 尤其是与高脂肪饮食或饮酒等饮食压力相结合时, 小鼠肠道屏障完整性功能遭到破坏, 使得肠道中促炎细菌数量的增加, 产生丁酸盐的细菌的减少或者拟杆菌/厚壁菌比例的改变, 进而造成肠道微生物群落的生物失调, 触发或促进相关疾病的发生^[17]。Kuang等^[18]研究表明肠道菌群控制宿主小肠上皮细胞的营养摄入和代谢的昼夜节律性。在该过程中, 组蛋白脱乙酰酶3 (HDAC3)整合肠道菌群和光暗节律信号, 是调控代谢基因节律性表达的关键因子。

2.2 抗生素、益生菌对肠道菌群的影响

抗生素影响细菌在胃肠道的生长和定植, 大多数抗生素干扰肠道微生物群的组成和酶活性, 并能抑制肠道微生物酶活性超过3天^[19]。Kim等^[20]研究描述了氨苄西林对大鼠肠道微生物数量的变化, 氨苄西林治疗明显减少肠球菌、肠杆菌和乳酸杆菌的数量, 而梭状芽孢杆菌的数量没有改变。16S rRNA焦磷酸测序分析表明, 氨苄西林治疗显著减少了肠道微生物群的数量和品种, 在门静脉期, 造成厚壁菌显著减少, 变形杆菌增多。抗生素影响肠道微生物群的代谢活动可以改变由肠道微生物群代谢的共同给药药物的药代动力学。通常认为药物药代动力学(吸收、分布、代谢和排泄)的改变是由于抑制或诱导药物代谢酶, 如细胞色素P450酶或参与吸收和排泄的转运蛋白。然而, 肠道微生物酶活性的调节是药物相互作用的另一个可能的原因。Zhang等^[21]研究了肠道菌群介导的阿莫西林与阿司匹林相互作用, 当大鼠给予阿莫西林后, 显著减少了幽门螺杆菌和普氏菌的丰度, 而且, 当阿司匹林与空白大鼠粪便提取液、阿莫西林处理组粪便提取液分别孵育12、24和36 h时, 阿司匹林的剩余量随时间的延长不断减少, 代谢产物水杨酸的生成量不断增加, 且阿莫西林处理组阿司匹林的量下降和水杨酸的生成缓慢, 表明肠道微生物群参与了阿司匹林的代谢, 且在给予阿莫西林后, 肠道微生物群对其代谢减慢。另外, 当阿莫西林和阿司匹林共同给药时, 水杨酸曲线下的面积增加了91.38%, 峰值浓度增加了60.43%, 清除率下降了43.55%, 结果表明, 阿莫西林与阿司匹林合用时, 由肠道菌群介导的相互作用不容忽视, 这可能是影响药物疗效的重要因素之一。

益生菌被认为是有益的微生物, 对便秘、腹泻、结肠炎和糖尿病显示出有益的治疗作用, 而对肠道微生物群有害菌的产生有抑制作用^[22]。因此, 临床益生菌的使用正在增加, 最重要的是它可以同时作为药物治疗。Kim等^[23]研究了口服益生菌对小鼠粪便微生物群的组成, 路氏乳杆菌增加了梭菌, 双歧杆菌和肠球菌的数量, 而鼠李糖乳杆菌通过在选择性培养基中培养降低了双歧杆菌的数量, 且口服路氏乳杆菌降低了对乙酰氨基酚的药时曲线下面积。口服益生菌可能改变肠道微生物群组成和酶活性, 因此, 益生菌与药物的共同使用可能导致药物的药代动力学参数的改变。

2.3 高原环境对肠道菌群的影响

低氧、低压、强紫外线和寒冷是高原环境的主要特征, 急剧变化的环境条件是导致肠黏膜损伤的关键因素。那么, 肠黏膜屏障作为机体发挥防御功能的防线之一, 可以保护机体不受内源性微生物及其毒素的伤害。高海拔地区的环境条件能使机体的免疫功能受损, 从而加大了细菌、毒素经肠道入侵机体的风险, 可能会导致菌群失调, 菌群失调又会对免疫屏障功能作用的正常发挥造成影响。Yang等^[24]通过实验证明, 高原缺氧会引起大鼠肠道菌群pH、肿瘤坏死因子以及白介素因子的改变, 且海拔越高, 菌群失调和细胞因子浸润更显著。Zhang等^[25]通过16S rRNA焦磷酸测序分析发现大鼠急进高原后, Venn图结果表明平原组OTU数目为218+299种, 高原组为87+299种, 与平原组相比, 高原组OTU数目显著下降。Alpha多样性结果表明高原环境显著减少了肠道菌群的种类和数量。物种及其丰度分析结果表明, 在属的水平上, 与平原组相比, 高原缺氧组拟杆菌、棒状杆菌、普氏菌、粪球菌属变化显著, 且具有显著性差异。Ma等^[26]也证明在低氧环境下, SD大鼠肠道微生物群落的结构和多样性是呈动态变化的, 且普氏菌和拟杆菌显著增加, 这可能与新陈代谢有关, 有利于机体适应低氧环境。Han等^[27]通过实地研究赴多巴国家高原训练基地在训运动员在进驻高原前和高原训练过程中的粪便样品, 结果表明, 运动员进驻高原后, 肠道菌群微生物多样性及群落丰度减少, 但没有显著性差异, 在门水平上呈现出拟杆菌门占比先上升后恢复、厚壁菌门占比先下降后恢复, 在其他菌的增殖和定植下, 有益菌占比减少, 肠道菌群平衡被打破。因此, 高原缺氧环境是影响肠道微生物稳态的一个重要影响因素, 尤其是进入高原的首日, 这或许可以解释急进高原人群出现恶心呕吐、消化不良及肠胃胀气等消化系统不适反应。

2.4 其他

肠道菌群的组成以及特定的细菌种类除了受到昼夜节律、益生菌、抗生素、缺氧环境的影响之外, 还受到pH值、组织的氧化还原电位和肠道运输时间等影响^[28]。低pH值为细菌的栖息和生长提供了恶劣的环境, 从而限制细菌物种的多样性。氧化还原电位对肠道细菌的数量和种类也会干扰, 氧化还原电位较低的区域有利于细菌的生长, 细菌将碳水化合物主动代谢为短链脂肪酸^{[29, 30]}。胃肠道运输时间也与细菌的生长和代谢有关, 人体平均全肠运输时间是70 h^[31]。尽管个体的转运时间各不相同, 但通常在大肠中花费的时间最长, 使得小肠中的细菌代谢低于大肠中的细菌代谢^[32]。

3 肠道菌群的功能

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随着高通量测序和代谢组学的突破, 人们逐渐认识到肠道菌群对机体的潜在重要性。它参与了基本维生素、氨基酸的合成, 如维生素B3、B5、B6、B12、K、生物素、四氢叶酸和氨基酸^[33] (蛋氨酸和色氨酸), 同时还能促进铁、镁、锌等矿物元素的吸收。正常菌群有许多重要的生理功能:如拮抗作用、免疫作用、排毒作用、抗肿瘤作用、抗衰老作用等, 并且可能与发病机制相关, 例如心脑血管疾病^[34]、肥胖和糖尿病^[35]、动脉粥样硬化^[36]等。

肠道菌群不仅对于维持机体健康十分重要, 而且还参与药物代谢来维持机体稳态平衡, 特别是口服药物, 因为药物通过肠道菌群代谢可能产生不同于宿主器官产生的代谢产物。如果由肠道菌群产生的代谢产物具有新的特征和生物活性, 这更值得关注。口服药物通过胃肠道吸收进入血液, 吸收取决于药物的溶解度、稳定性和通透性以及由身体和肠道微生物群分泌的酶的代谢^[37]。异生素代谢是指包括人类在内的生物体对药物或食物成分的生物化学修饰。该方法通常将疏水性异生化合物转化为更亲水的产物以促进其排泄^[38]。肝脏是异种生物代谢的主要部位, 然而, 口服给药的异生化合物也可能被肠道微生物酶代谢, 然后从胃肠道吸收到血液中。

4 肠道菌群对药物代谢的影响

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药物微生物组学研究肠道微生物群变化对药物药代动力学和药效学的影响。通常情况下, 药物主要从小肠吸收, 而与肠道内的微生物没有太大关联, 肠道细菌代谢的速率和程度受到达远端肠道的药物量以及肠道微生物群落的组成和驻留细菌产生的特定酶的影响^[39]。大多数药物与肠道微生物群几乎没有接触, 因为它们被上消化道迅速而完全地吸收^[40]。然而, 一些药物被肠道微生物群转化为活性、非活性或毒性代谢物, 这些微生物大多位于回肠和结肠。将肠道微生物群影响药物药代动力学主要分为以下几方面:

4.1 微生物介导的前药活化

肠道微生物介导的前药活化最经典的是基于磺胺的偶氮抗菌前药如偶氮磺胺(百浪多息)、偶氮磺酰胺以及一系列治疗溃疡性结肠炎的5-氨基水杨酸前药, 如柳氮磺吡啶、奥沙拉嗪、巴柳氮^[41]。通过肠道菌群激活了活性磺胺代谢产物, 表明微生物参与了磺胺类药物的生物活化^[42]。研究者在大鼠身上进行了临床前研究, 发现给予抗生素之后再给药, 将减少前药百浪多息转化为磺胺, 这可能是抗生素干扰了微生物代谢。如果给予一个疗程的抗生素, 可能会降低某些共同给药的药物的治疗效果。同样, 个体间肠道菌群组成的差异性可能潜在地决定了前药转化的效力。在结肠中, 柳氮磺吡啶的偶氮键被细菌偶氮还原酶分解为磺胺吡啶和5-氨基水杨酸。当给予抗生素或用无菌大鼠时, 柳氮磺吡啶没有被代谢^[43]。因此, 如果肠道菌群发生改变, 那么可能会影响柳氮磺胺吡啶激活和最终疗效。研究^[44]报道益生菌治疗会显著增加结肠内容物中柳氮磺吡啶的还原反应。因此, 可以更好地利用肠道菌群以实现特定部位的药物释放。洛伐他汀是一种在体内易于水解产生活性双羟基酸代谢物的内酯前体药物, 洛伐他汀与人和大鼠粪便酶制剂的孵育产生4种代谢物M1 (去甲基丁酰基代谢物)、M4 (羟基化代谢物)、M8 (活性羟基酸代谢物)和M9 (羟化M8), 表明肠道微生物群参与洛伐他汀代谢。此外, 给予抗生素后, 与对照组相比, 抗生素治疗时大鼠血浆中活性羟基酸代谢物明显降低, 且大鼠中粪便羟基酸代谢物的形成也显著减少^[45]。因此, 在临床中抗生素的长期使用可能会影响药物的治疗效果和增加了治疗风险。Matuskova等^[46]研究了益生菌大肠杆菌菌株Nissle (EcN)影响了抗心律失常药物胺碘酮(AMI)的药代动力学并提高了AMI的生物利用度。他们发现EcN与AMI共同给药时, 与对照组相比, AMI的AUC增加了43%。但是, 如果益生菌EcN被非益生素E. coli菌株替代, 并未观察到显著变化。因此, EcN的共同给药使药物更好地从胃肠道吸收, 推测可能是降低了小肠pH从而促进了分子的解离和黏膜转运。或者, 摄取型转运蛋白OATP2B1的表达促进了AMI的吸收。

4.2 微生物介导的药物失活

地高辛是一种用于各种急性和慢性心功能不全以及室上性心动过速、心房颤动和扑动等的强心苷类药物, 其作用机制是作为钠钾ATP酶抑制剂使心肌细胞内钙离子浓度增加, 使心肌收缩力增加, 增加心输出量改善心功能。但是地高辛的药物活性受到肠道菌群的影响, 地高辛可以通过结肠中的细菌转化为非活性代谢产物二氢地高辛, 从而使与心肌细胞的Na-K-ATP酶结合不良无法兴奋心脏活动。此外, 当同时给予抗生素干预时, 血浆中地高辛的浓度增加而尿液中二氢地高辛的浓度降低, 这进一步证明地高辛的代谢与肠道微生物群紧密相关^[47]。最新研究表明, Eggerthella lenta的细胞色素编码操纵子被地高辛转录激活, 称为“强心苷还原酶” (cgr)操纵子, 是地高辛灭活的预测因子^[48]。因此, 肠道微生物对地高辛的灭活使其药代动力学参数未达到预测的浓度, 而且对肠道微生物介导的地高辛的代谢机制的阐明, 有助于进一步了解肠道微生物对药代动力学的影响, 这将为临床应用中通过调控肠道微生物群来降低药物毒性奠定基础。

4.3 微生物介导的宿主药物产生毒性

微生物介导的异生物代谢可能对宿主产生不良影响, 使药物的临床适用性受到限制。伊立替康(CPT-11)是一种静脉注射制剂, 在临床上主要用于大肠癌的治疗, CPT-11被宿主组织中的羧酸酯酶转化为活性的SN-38, SN-38是肿瘤细胞中拓扑异构酶I的抑制剂, 在分泌入肠之前, SN-38通过肝脏中的UDP-葡萄糖醛酸转移酶结合成SN-38-G, 然而, 无毒的SN-38-G可以通过肠道菌群中的β-葡萄糖醛酸酶转化为SN-38从而引起严重的腹泻。其中抗肿瘤拓扑异构酶I抑制剂SN-38与腹泻相关, 此过程产生的毒性归因于微生物β-葡萄糖醛酸酶^[49]。因此, 抑制β-葡萄糖醛酸酶的活性可以减少不良反应。抗生素治疗可通过抑制肠道菌群显著降低CPT-11的肠道不良反应。此外, 研究人员发现了一种有效的β-葡萄糖醛酸酶抑制剂, 可以有效减轻CPT-11-引起的腹泻并通过减少细胞炎症来保护肠道组织。SN-38介导的毒性通过选用选择性微生物β-葡萄糖醛酸酶抑制剂是提高患者治疗效果的有效途径, 并能扩展静脉注射与口服给药的治疗范围^[50]。微生物β-葡萄糖醛酸酶的小分子抑制剂改善药物的耐受性也适用于其他非甾体抗炎药物。Liang等^[51]进一步证明了改变肠道微生物将影响吲哚美辛的药代动力学和相应的疗效。抗生素使β-葡萄糖醛酸酶耗尽导致吲哚美辛的重吸收减少, 从而加速了吲哚美辛的排泄和缩短了半衰期。扑热息痛是一种广泛应用的解热镇痛药, 但是, 过量的扑热息痛引起肝毒性非常常见, 它在肝脏内代谢主要通过两个途径:葡萄糖醛酸化和硫酸化。对甲酚和对乙酰氨基酚都是肝磺基转移酶的底物, 因此, 对甲酚水平高可能是因为竞争性磺化减少了扑热息痛的代谢。如果病人携带着大量的对甲酚可能增加肝毒性的风险^[52]。同时, 研究^[25]发现益生菌的摄入会使扑热息痛的吸收波动, 因为肠道微生物介导的药物代谢紊乱, 并且随后对微生物代谢的影响可能导致药物全身浓度改变。由此可知, 鉴定微生物潜在地精确干预机制可以消除药物带来的不利影响和提高药物的耐受性。

肠道菌群对药物代谢的影响总结见表 1^{[27, 43, 45, 46, 50, 52-68]}。

5 高原环境肠道菌群介导的药物药代动力学的变化

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机体在高原缺氧环境中会发生一些变化, 具体表现在生理、生化、病理性等方面, 如血气、血流动力学、各项生化指标以及主要脏器功能的改变, 这些改变会干扰药物在体内的吸收、分布、代谢和排泄的药代动力学过程, 进而可能对药物的临床疗效和安全性造成影响^[69]。前期研究^[70]发现, 大鼠急进玛多后, 服用美托洛尔生物利用度降低, 如果需要维持正常血药浓度, 急进大鼠的美托洛尔剂量应该增加, 给药间隔应适当延长。大鼠急进玛多后, 体内氨茶碱的生物利用度增加, 达峰时间(t_max)减小, 说明急进高原后氨茶碱吸收较快。综合大鼠药代动力学结果, 急进高原后, 氨茶碱的用药剂量应适当降低, 以防止体内浓度过高, 增加药物对人体的不良反应^[71]。莫沙必利急进玛多组与平原组比较, AUC增加2倍, 表明大鼠急进玛多后, 莫沙必利的生物利用度增加, 而峰浓度(C_max)和t_max增加不明显, 平均驻留时间(MRT)增加, 表明大鼠体内药物的消除减慢, 如需维持相同的血药浓度, 莫沙必利的给药间隔可适当延长^[72]。国外学者在高原药代动力学方面报道的文献也有许多。Ritschel等^[73]研究了长期和短期暴露于高原环境下乙酰唑胺的药代动力学变化, 研究对象为年轻健康男性志愿者, 发现高海拔急进组人员服用乙酰唑胺后清除速率常数显著高于海平面组, 生物利用度也明显升高, 并且这种变化在生活10个月之久的研究人群中更为显著, 急进高原组表观分布体积较平原组下降17%, 高原长期暴露组较急进高原组增加了37%, 这些数据提示在前往高海拔地区时, 需要调整乙酰唑胺的剂量来有效预防急性高山病。Arancibia等^[74]研究了健康志愿者暴露于高海拔地区时体内碳酸锂的药代动力学的变化, 发现人体在高原地区血细胞比容和红细胞计数(RBC)均显著增加, 且血浆清除率下降, 提示在高原地区碳酸锂的药代动力学会发生变化, 并且这些变化与临床指标相关。高原缺氧环境引起药物药代动力学的变化的原因十分复杂, 除了受到代谢酶, 转运蛋白以及核受体的调节之外, 高原缺氧导致肠道菌群失衡也是引起药物药代动力学发生变化的一个重要影响因素。

众多研究已证明, 高原缺氧导致肠黏膜损伤, 进而导致胃肠道微生态环境失衡, 肠道菌群的组成和数量发生显著变化, 那么, 肠道微生物群的任何改变或生态失调都可以直接或间接地影响微生物介导的药物生物活化, 从而, 进一步影响药物的药动学和药效学。Zhang等^[75]研究了大鼠急进高原缺氧环境, 肠道菌群介导的硝苯地平药代动力学的变化, 首次通过体外实验证实肠道菌群参与了硝苯地平的代谢过程, 更重要的是, 这些菌群的变化可能导致大鼠急进高原口服硝苯地平后, 与平原组相比, 药时曲线下面积(AUC)显著增加39.10%, 在急进高原期后体内代谢活动变慢, 从而提高了硝苯地平的生物利用度和治疗效果。之后, 阿莫西林与硝苯地平的相互作用研究进一步证明, 当给予阿莫西林后, 硝苯地平的代谢减慢, AUC增加了39.10%, t_max提前了0.45 h, CL降低了34.71%^[76], 说明二者合用可能会增强硝苯地平的治疗效果, 肠道菌群介导的药物-药物相互作用应当引起重视。

6 研究展望

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人肠道菌群基因数量是人基因数量的38倍之多, 其代谢能力不容小觑。传统的药物基因组学主要是研究不同个体遗传因素对药物代谢和药物疗效的影响, 药物代谢过程涉及基因控制下合成的各种蛋白质, 如药物代谢酶、药物转运蛋白、受体和靶蛋白等, 而忽略了庞大的微生物组的贡献。药代动力学应当将药物基因组学与微生物组学相结合, 从而更全面的预测药物反应, 或改变菌群以改善药效, 促进个性化医疗。目前的研究还需要进一步明确微生物和药物相互作用的机制, 通过干预特定的细菌产生的酶对于疾病的预防和治疗有着重大意义。更重要的是, 由于高原合理用药会受到肠道菌群的影响, 因此, 在调整高原用药剂量时应当考虑其在药物代谢中发挥的作用。

作者贡献:孙月梅参与论文撰写工作, 王荣参与论文框架设计工作, 李文斌参与论文修改工作, 张雅婷参与论文中图表绘制工作, 张娟红参与文献查阅工作, 李雪参与文献整理工作。

利益冲突:所有作者申明不存在任何潜在的利益冲突。

基金

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国家自然科学基金资助项目(81673508)
全军后勤科研“十二五”计划面上项目(CWH17J012)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

Enright

, Gahan

, Joyce

et al . The impact of the gut microbiota on drug metabolism and clinical outcome[J]. Yale J Biol Med, 2016, 89: 375-382. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045146/

[2]

Saad

, Rizkallah

, Aziz

. Gut Pharmacomicrobiomics:the tip of an iceberg of complex interactions between drugs and gut-associated microbes[J]. Gut Pathog, 2012, 4: 16.

https://doi.org/10.1186/1757-4749-4-16

[3]

Sousa

, Paterson

, Moore

et al . The gastrointestinal microbiota as a site for the biotransformation of drugs[J]. Int J Pharm, 2008, 363: 1-25.

https://doi.org/10.1016/j.ijpharm.2008.07.009

[4]

Eckburg

, Bik

, Bernstein

et al . Diversity of the human intestinal microbial flora[J]. Science, 2005, 308: 1635-1638.

https://doi.org/10.1126/science.1110591

[5]

Wang

, Ahrné

, Jeppsson

et al . Comparison of bacterial diversity along the human intestinal tract by direct cloning and sequencing of 16S rRNA genes[J]. FEMS Microbiol Ecol, 2005, 54: 219-231.

https://doi.org/10.1016/j.femsec.2005.03.012

[6]

Rodríguez

, Murphy

, Stanton

et al . The composition of the gut microbiota throughout life, with an emphasis on early life[J]. Microb Ecol Health Dis, 2015, 26: 26050. http://europepmc.org/articles/PMC4315782/

[7]

Biasucci

, Rubini

, Riboni

et al . Mode of delivery affects the bacterial community in the newborn gut[J]. Early Hum Dev, 2010, 86 Suppl 1 13-15. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=7605356f6824e4a7573267b3bc225081

[8]

Claesson

, Cusack

, O'Sullivan

et al . Composition, variability, and temporal stability of the intestinal microbiota of the elderly[J]. Proc Natl Acad Sci U S A, 2011, 108 Suppl 1 4586-4591.

[9]

Dethlefsen

, Relman

. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation[J]. Proc Natl Acad Sci U S A, 2011, 108 Suppl 1 4554-4561. http://gut.bmj.com/cgi/ijlink?linkType=ABST&journalCode=pnas&resid=108/Supplement_1/4554

[10]

Manichanh

, Reeder

, Gibert

et al . Reshaping the gut microbiome with bacterial transplantation and antibiotic intake[J]. Genome Res, 2010, 20: 1411-1419.

https://doi.org/10.1101/gr.107987.110

[11]

Scarpellini

, Ianiro

, Attili

et al . The human gut microbiota and virome:potential therapeutic implications[J]. Dig Liver Dis, 2015, 47: 1007-1012.

https://doi.org/10.1016/j.dld.2015.07.008

[12]

Voigt

, Forsyth

, Green

et al . Circadian disorganization alters intestinal microbiota[J]. PLoS One, 2014, 9: e97500.

https://doi.org/10.1371/journal.pone.0097500

[13]

Hastings

, Reddy

, Maywood

. A clockwork web:circadian timing in brain and periphery, in health and disease[J]. Nat Rev Neurosci, 2003, 4: 649-661.

[14]

Leone

, Gibbons

, Martinez

et al . Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism[J]. Cell Host Microbe, 2015, 17: 681-689.

https://doi.org/10.1016/j.chom.2015.03.006

[15]

Thaiss

, Zeevi

, Levv

et al . Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis[J]. Cell, 2014, 159: 514-529.

https://doi.org/10.1016/j.cell.2014.09.048

[16]

Liang

, Bushman

, Fitzgerald

. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock[J]. Proc Natl Acad Sci U S A, 2015, 112: 10479-10484.

https://doi.org/10.1073/pnas.1501305112

[17]

Voigt

, Forsyth

, Green

et al . Circadian rhythm and the gut microbiome[J]. Int Rev Neurobiol, 2016, 131: 193-205.

https://doi.org/10.1016/bs.irn.2016.07.002

[18]

Kuang

, Wang

, Li

et al . The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3[J]. Science, 2019, 365: 1428-1434.

https://doi.org/10.1126/science.aaw3134

[19]

Yoo

, Kim

, Van

Le TK

et al . Gut microbiota-mediated drug interactions between lovastatin and antibiotics[J]. Drug Metab Dispos, 2014, 42: 1508-1513.

https://doi.org/10.1124/dmd.114.058354

[20]

Kim

, Yoo

, Jung

et al . Reduced metabolic activity of gut microbiota by antibiotics can potentiate the antithrombotic effect of aspirin[J]. Biochem Pharmacol, 2016, 122: 72-79.

https://doi.org/10.1016/j.bcp.2016.09.023

[21]

Zhang

, Sun

, Wang

et al . Gut microbiota-mediated drug-drug interaction between amoxicillin and aspirin[J]. Sci Rep, 2019, 9: 16194.

https://doi.org/10.1038/s41598-019-52632-5

[22]

Kleerebezem

, Binda

, Bron

et al . Understanding mode of action can drive the translational pipeline towards more reliable health benefits for probiotics[J]. Curr Opin Biotechnol, 2019, 56: 55-60.

https://doi.org/10.1016/j.copbio.2018.09.007

[23]

Kim

, Choi

, Jeong

et al . Effect of probiotics on pharmacokinetics of orally administered acetaminophen in mice[J]. Drug Metab Dispos, 2018, 46: 122-130.

https://doi.org/10.1124/dmd.117.077222

[24]

Yang

, Zhang

, Wu

et al . Study on intestinal microecological changes in radical plateau rats[J]. Chin J Gastroenterol Hepatol (胃肠病学和肝病学杂志), 2010, 19: 543-545. http://www.cabdirect.org/abstracts/20103084291.html

[25]

Zhang

, Chen

, Sun

et al . Plateau hypoxia attenuates the metabolic activity of intestinal flora to enhance the bioavailability of nifedipine[J]. Drug Deliv, 2018, 25: 1175-1181.

https://doi.org/10.1080/10717544.2018.1469687

[26]

, Ma

, Shang

et al . Effects of hypoxic exposure on rats' gut microbiota[J]. Microbiol China (微生物学通报), 2019, 46: 120-129. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=wswxtb201901014

[27]

Han

, Hu

, Zhang

et al . Athletes' diarrhea occurrence and changes of intestinal microbial flora in high altitude training[J]. Prog Mod Biomed (现代生物医学进展), 2018, 18: 1909-1915. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=swcx201810022

[28]

Kim

. Gut microbiota-mediated drug-antibiotic interactions[J]. Drug Metab Dispos, 2015, 43: 1581-1589.

https://doi.org/10.1124/dmd.115.063867

[29]

Aguilera

, Vergara

, Martínez

. Stress and antibiotics alter luminal and wall-adhered microbiota and enhance the local expression of visceral sensory-related systems in mice[J]. Neurogastroenterol Motil, 2013, 25: e515-e529.

https://doi.org/10.1111/nmo.12154

[30]

, Xu

, Chen

et al . Regulation of an antioxidant blend on intestinal redox status and major microbiota in early weaned piglets[J]. Nutrition, 2014, 30: 584-589.

https://doi.org/10.1016/j.nut.2013.10.018

[31]

Cummings

, Bingham

, Heaton

et al . Fecal weight, colon cancer risk, and dietary intake of nonstarch polysaccharides (dietary fiber)[J]. Gastroenterology, 1992, 103: 1783-1789.

https://doi.org/10.1016/0016-5085(92)91435-7

[32]

Varum

, McConnell

, Sousa

et al . Mucoadhesion and the gastrointestinal tract[J]. Crit Rev Ther Drug Carrier Syst, 2008, 25: 207-258.

https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v25.i3.10

[33]

Wallace

, Redinbo

. The human microbiome is a source of therapeutic drug targets[J]. Curr Opin Chem Biol, 2013, 17: 379-384.

https://doi.org/10.1016/j.cbpa.2013.04.011

[34]

Singh

, Yeoh

, Vijay-Kumar

. Gut microbiome as a novel cardiovascular therapeutic target[J]. Curr Opin Pharmacol, 2016, 27: 8-12.

https://doi.org/10.1016/j.coph.2016.01.002

[35]

Forslund

, Hildebrand

, Nielsen

et al . Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota[J]. Nature, 2015, 528: 262-266.

https://doi.org/10.1038/nature15766

[36]

Koeth

, Wang

, Levison

et al . Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis[J]. Nat Med, 2013, 19: 576-585.

https://doi.org/10.1038/nm.3145

[37]

Al-Hilal

, Alam

, Byun

. Oral drug delivery systems using chemical conjugates or physical complexes[J]. Adv Drug Deliv Rev, 2013, 65: 845-864.

https://doi.org/10.1016/j.addr.2012.11.002

[38]

Croom

. Metabolism of xenobiotics of human environments[J]. Prog Mol Biol Transl Sci, 2012, 112: 31-88.

https://doi.org/10.1016/B978-0-12-415813-9.00003-9

[39]

Aidy S

, Van

den Bogert B

, Kleerebezem

. The small intestine microbiota, nutritional modulation and relevance for health[J]. Curr Opin Biotechnol, 2015, 32: 14-20.

https://doi.org/10.1016/j.copbio.2014.09.005

[40]

Kim

. Gut microbiota-mediated drug-antibiotic interactions[J]. Drug metab dispos, 2015, 43: 1581-1589.

https://doi.org/10.1124/dmd.115.063867

[41]

Wilson

, Nicholson

. Gut microbiome interactions with drug metabolism, efficacy, and toxicity[J]. Transl Res, 2017, 179: 204-222.

https://doi.org/10.1016/j.trsl.2016.08.002

[42]

Mani

, Boelsterli

, Redinbo

. Understanding and modulating mammalian-microbial communication for improved human health[J]. Annu Rev Pharmacol Toxicol, 2014, 54: 559-580.

https://doi.org/10.1146/annurev-pharmtox-011613-140007

[43]

Peppercorn

, Goldman

. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine[J]. J Pharmacol Exp Ther, 1972, 181: 555-562. http://www.ncbi.nlm.nih.gov/pubmed/4402374

[44]

, He

, Jia

. The influence of gut microbiota on drug metabolism and toxicity[J]. Expert Opin Drug Metab Toxicol, 2016, 12: 31-40.

https://doi.org/10.1517/17425255.2016.1121234

[45]

Yoo

, Kim

, Van

Le TK

et al . Gut microbiota-mediated drug interactions between lovastatin and antibiotics[J]. Drug Metab Dispos, 2014, 42: 1508-1513.

https://doi.org/10.1124/dmd.114.058354

[46]

Matuskova

, Anzenbacherova

, Vecera

et al . Administration of a probiotic can change drug pharmacokinetics:effect of E. coli Nissle 1917 on amidarone absorption in rats[J]. PLoS One, 2014, 9: e87150.

https://doi.org/10.1371/journal.pone.0087150

[47]

Lindenbaum

, Rund

, Butler

et al . Inactivation of digoxin by the gut flora:reversal by antibiotic therapy[J]. N Engl J Med, 1981, 305: 789-794.

https://doi.org/10.1056/NEJM198110013051403

[48]

Saha

, Butler

, Neu

et al . Digoxin-inactivating bacteria:identification in human gut flora[J]. Science, 1983, 220: 325-327.

https://doi.org/10.1126/science.6836275

[49]

Wallace

, Wang

, Lane

et al . Alleviating cancer drug toxicity by inhibiting a bacterial enzyme[J]. Science, 2010, 330: 831-835.

https://doi.org/10.1126/science.1191175

[50]

Kehrer

, Sparreboom

, Verweij

et al . Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients[J]. Clin Cancer Res, 2001, 7: 1136-1141. http://www.ncbi.nlm.nih.gov/pubmed/11350876/

[51]

Liang

, Bittinger

, LI

et al . Bidirectional interactions between indomethacin and the murine intestinal microbiota[J]. Elife, 2015, 4: e08973.

https://doi.org/10.7554/eLife.08973

[52]

Clayton

, Baker

, Lindon

et al . Pharmacometabonomic identification of a significant hostmicrobiome metabolic interaction affecting human drug metabolism[J]. Proc Natl Acad Sci U S A, 2009, 106: 14728-14733.

https://doi.org/10.1073/pnas.0904489106

[53]

Gingell

, Bridges

, Williams

. The role of the gut flora in the metabolism of prontosil and neoprontosil in the rat[J]. Xenobiotica, 1971, 1: 143-156.

https://doi.org/10.3109/00498257109044386

[54]

Wadworth

, Fitton

. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in inflammatory bowel disease[J]. Drugs, 1991, 41: 647-664.

https://doi.org/10.2165/00003495-199141040-00009

[55]

Chan

, Pope

, Gilbert

et al . Studies of two novel sulfasalazine analogs, ipsalazide and balsalazide[J]. Dig Dis Sci, 1983, 28: 609-615.

https://doi.org/10.1007/BF01299921

[56]

Kaddurah-Daouk

, Baillie

, Zhu

et al . Enteric microbiome metabolites correlate with response to simvastatin treatment[J]. PLoS One 6: e25482.

https://doi.org/10.1371/journal.pone.0025482

[57]

Haiser

, Gootenberg

, Chatman

et al . Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta[J]. Science, 2013, 341: 295-298.

https://doi.org/10.1126/science.1235872

[58]

Saitta

, Zhang

, LEE

et al . Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac:mode of action and pharmacokinetics[J]. Xenobiotica, 2014, 44: 28-35.

https://doi.org/10.3109/00498254.2013.811314

[59]

Tozaki

, Emi

, Horisaka

et al . Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents:implications in peptide delivery to the colon[J]. J Pharm Pharmacol, 1997, 49: 164-168.

https://doi.org/10.1111/j.2042-7158.1997.tb06773.x

[60]

Hashim

, Azmin

, Razlan

et al . Eradication of Helicobacter pylori infection improves levodopa action, clinical symptoms and quality of life in patients with Parkinson's disease[J]. PLoS One, 2014, 9: e112330.

https://doi.org/10.1371/journal.pone.0112330

[61]

Koch

, Goldman

. The anaerobic metabolism of metronidazole forms n-(2-hydroxyethyl)-oxamic acid[J]. J Pharmacol exp Ther, 1979, 208: 406-410. http://europepmc.org/abstract/MED/430360

[62]

Takeno

, Sakai

. Involvement of the intestinal microflora in nitrazepam-induced teratogenicity in rats and its relationship to nitroreduction[J]. Teratology, 1991, 44: 209-214.

https://doi.org/10.1002/tera.1420440209

[63]

Mosa

, Hutter

, Zapp

et al . Regioselective acetylation of C21 hydroxysteroids by the bacterial chloramphenicol acetyltransferase I[J]. Chembiochem, 2015, 16: 1670-1679.

https://doi.org/10.1002/cbic.201500125

[64]

Basit

, Newton

, Lacey

. Susceptibility of the H2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora[J]. Int J Pharm, 2002, 237: 23-33.

https://doi.org/10.1016/S0378-5173(02)00018-2

[65]

Basit

, Lacey

. Colonic metabolism of ranitidine:implications for its delivery and absorption[J]. Int J Pharm, 2001, 227: 157-165.

https://doi.org/10.1016/S0378-5173(01)00794-3

[66]

Meuldermans

, Hendrickx

, Mannens

et al . The metabolism and excretion of risperidone after oral administration in rats and dogs[J]. Drug Metab Dispos, 1994, 22: 129-138. http://www.ncbi.nlm.nih.gov/pubmed/7512019

[67]

Yoo

, Kim

, Yoo

et al . Effects of orally administered antibiotics on the bioavailability of amlodipine:gut microbiota-mediated drug interaction[J]. J Hypertens, 2016, 34: 156-162.

https://doi.org/10.1097/HJH.0000000000000773

[68]

Shu

, Kingston

, Van

Tassell RL

et al . Metabolism of levamisole, an anti-colon cancer drug, by human intestinal bacteria[J]. Xenobiotica, 1991, 21: 737-750.

https://doi.org/10.3109/00498259109039513

[69]

Nian

, Xin

, Zhou

et al . Research progress on the physiological effects of plateau hypoxic environment on the human body and human pharmacokinetic characteristics[J]. Pharm Res (药学研究), 2018, 37: 42-47.

[70]

Zhang JH, Wang R, Xie H. Effects of plateau environment on pharmacokinetics of β-receptor blockers[C]//2013 Chinese Pharmacy Conference and the 13th Chinese Pharmacist Week Proceedings (2013年中国药学大会暨第十三届中国药师周论文集). Nanning: Chinese Pharmaceutical Association, 2013: 1108-1123.

[71]

Zhang

. Comparison of pharmacokinetics of aminophylline in rats after plain and rapid plateau[J]. J High Altitude Med (高原医学杂志), 2017, 27: 8.

[72]

Zhang

, Xiang

, Wang

. Comparative study of pharmacokinetics of moxapride in rats under different environmental conditions[J]. Med Pharm J Chin PLA (解放军医药杂志), 2013, 25: 24-27.

[73]

Ritschel

, Paulos

, Arancibia

et al . Pharmacokinetics of acetazolamide in healthy volunteers after short-and long-term exposure to high altitude[J]. J Clin Pharmacol, 1998, 38: 533-539.

https://doi.org/10.1002/j.1552-4604.1998.tb05791.x

[74]

Arancibia

, Paulos

, Chávez

et al . Pharmacokinetics of lithium in healthy volunteers after exposure to high altitude[J]. Int J Clin Pharmacol Ther, 2003, 41: 200-206.

https://doi.org/10.5414/CPP41200

[75]

Zhang

, Zhang

, Wang

. Gut microbiota modulates drug pharmacokinetics[J]. Drug Metab Rev, 2018, 50: 357-368.

https://doi.org/10.1080/03602532.2018.1497647

[76]

Zhang

, Wang

, Zhao

et al . Interaction of amoxicillin and nifedipine mediated by intestinal flora[J]. Acta Pharm Sin (药学学报), 2018, 53: 1721-1725 http://www.yxxb.com.cn:8081/aps/CN/abstract/abstract17289.shtml

2020年第55卷第10期

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doi: 10.16438/j.0513-4870.2020-0455

接收时间：2020-04-01
首发时间：2026-01-23
出版时间：2020-10-12

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收稿日期：2020-04-01
修回日期：2020-05-20

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国家自然科学基金资助项目(81673508)

全军后勤科研“十二五”计划面上项目(CWH17J012)

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1.中国人民解放军联勤保障部队第九四〇医院, 全军高原医学重点实验室, 甘肃兰州 730050

2.兰州大学药学院, 甘肃兰州 730000

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*王荣,Tel: 86-931-8994675, E-mail: wangrong-69@163.com;

李文斌,Tel: 86-931-8994675, E-mail: yfcs2002@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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BibTeX
EndNote
RefWorks
TxT

Typical drug	Clinical use	Influence on drugs	Pharmacological/toxicological consequence	Related bacteria/ enzyme	Ref.
Sulfasalazine	Sulfonamides	Metabolism↑	Toxicity↑ (prodrug activation to sulfapyridine and 5-aminosalicylic acid)	Azoreductase Enzymes	^[43]
Prontosil	Sulfonamides	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[53]
Olsalazine	Treatment of ulcerative colitis	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[54]
Balsalazide	Treatment of ulcerative colitis	Metabolism↑	Activity↑ (prodrug activation)	Azoreductase Enzymes	^[55]
Lovastatin	Antihyperlipidemic drugs	Metabolism↑	Activity↑ (prodrug activation as active hydroxy acid metabolite)	Not reported	^[45]
Simvastatin	Antihyperlipidemic drugs	Metabolism↑	Activity↑	Lactobacillus	^[56]
Amiodarone	Antiarrhythmic drugs	AUC↑ Absorption↑	Activity↑	Escherichia coli Nissle 1917	^[46]
Digoxin	Anti-chronic cardiac insufficiency	Metabolism↑ (reduction reaction)	Cardiotonic effect↑	Eggerthella lenta	^[57]
Irinotecan	Treatment of colorectal cancer	Metabolism↑ Slow excretion	Toxicity↑ (SN-38 activity activated)	Escherichia coli, Bacteroides vulgatus and Clostridium ramosum, β-Glucuronidase enzymes	^[50]
Indomethacin	Anti-inflammatory analgesics	Metabolism↑ Slow excretion	Toxicity↑ (enterohepatic circulation)	β-Glucuronidase enzymes	^[58]
Acetaminophen	Antipyretic analgesics	Metabolism↓	Liver toxicity↑	Clostridium difficile	^[52]
Insulin	Hypoglycemic drugs	Metabolism↑	Activity↓ Blood sugar↓	Protease	^[59]
Levodopa	Anti-Parkinson's disease	Absorption↓ Metabolism↑	Activity↓	Helicobacter pylori	^[60]
Metronidazole	Anti-amoebiasis	AUC↓	Activity↓	Clostridium perfringens	^[61]
Nitrazepam	Benzodiazepine sedative hypnotics	Metabolism↑	Toxicity↑ (teratogenicity)	Nitroreductase Enzymes	^[62]
Chloramphenicol	Bacteriostatic broad- spectrum antibiotics	Metabolism↑	Toxicity↑	Not reported	^[63]
Nizatidine	Gastric acid secretion inhibitor	Metabolism↑	Activity↓	Not reported	^[64]
Ranitidine	Gastric acid secretion inhibitor	Metabolism↑	Activity↓	Not reported	^[65]
Risperidone	Antipsychotics	Metabolism↑	Activity↓	Not reported	^[66]
Amlodipine	Antihypertensive drugs	C_max↑AUC↑	Activity↑	Not reported	^[67]
Nifedipine	Antihypertensive drugs	AUC↑ Slow excretion	Activity↑	Not reported	^[27]
Levamisole	Intestinal repellent	Metabolism↓	Activity↑	Bacteroides, Clostridium species	^[68]

Typical drug

Clinical use

Influence on
drugs

Pharmacological/toxicological
consequence

Related bacteria/
enzyme

Ref.

Sulfasalazine

Sulfonamides

Metabolism↑

Toxicity↑
(prodrug activation to sulfapyridine
and 5-aminosalicylic acid)

Azoreductase
Enzymes

^[43]

Prontosil

Sulfonamides

Metabolism↑

Activity↑
(prodrug activation)

Azoreductase
Enzymes

^[53]

Olsalazine

Treatment of ulcerative
colitis

Metabolism↑

Activity↑
(prodrug activation)

Azoreductase
Enzymes

^[54]

Balsalazide

Treatment of ulcerative
colitis

Metabolism↑

Activity↑
(prodrug activation)

Azoreductase
Enzymes

^[55]

Lovastatin

Antihyperlipidemic
drugs

Metabolism↑

Activity↑
(prodrug activation as active
hydroxy acid metabolite)

Not reported

^[45]

Simvastatin

Antihyperlipidemic
drugs

Metabolism↑

Activity↑

Lactobacillus

^[56]

Amiodarone

Antiarrhythmic drugs

AUC↑
Absorption↑

Activity↑

Escherichia coli Nissle
1917

^[46]

Digoxin

Anti-chronic cardiac
insufficiency

Metabolism↑
(reduction reaction)

Cardiotonic effect↑

Eggerthella lenta

^[57]

Irinotecan

Treatment of colorectal
cancer

Metabolism↑
Slow excretion

Toxicity↑
(SN-38 activity activated)

Escherichia coli, Bacteroides
vulgatus and
Clostridium ramosum,
β-Glucuronidase
enzymes

^[50]

Indomethacin

Anti-inflammatory
analgesics

Metabolism↑
Slow excretion

Toxicity↑
(enterohepatic circulation)

β-Glucuronidase enzymes

^[58]

Acetaminophen

Antipyretic analgesics

Metabolism↓

Liver toxicity↑

Clostridium difficile

^[52]

Insulin

Hypoglycemic drugs

Metabolism↑

Activity↓
Blood sugar↓

Protease

^[59]

Levodopa

Anti-Parkinson's
disease

Absorption↓
Metabolism↑

Activity↓

Helicobacter pylori

^[60]

Metronidazole

Anti-amoebiasis

AUC↓

Activity↓

Clostridium perfringens

^[61]

Nitrazepam

Benzodiazepine
sedative hypnotics

Metabolism↑

Toxicity↑
(teratogenicity)

Nitroreductase
Enzymes

^[62]

Chloramphenicol

Bacteriostatic broad-
spectrum antibiotics

Metabolism↑

Toxicity↑

Not reported

^[63]

Nizatidine

Gastric acid secretion
inhibitor

Metabolism↑

Activity↓

Not reported

^[64]

Ranitidine

Gastric acid secretion
inhibitor

Metabolism↑

Activity↓

Not reported

^[65]

Risperidone

Antipsychotics

Metabolism↑

Activity↓

Not reported

^[66]

Amlodipine

Antihypertensive drugs

C_max↑AUC↑

Activity↑

Not reported

^[67]

Nifedipine

Antihypertensive drugs

AUC↑
Slow excretion

Activity↑

Not reported

^[27]

Levamisole

Intestinal repellent

Metabolism↓

Activity↑

Bacteroides,
Clostridium species

^[68]