肠道菌群代谢药物研究进展

长期以来,由于肠道菌群本身的复杂性以及培养方法和分析技术的限制,肠道菌群在药物代谢和体内处置中的作用未得到应有的重视。近年来,随着技术的快速发展,围绕肠道菌群的大量研究将对肠道菌代谢和肠道菌-宿主共代谢的认识提高到前所未有的深度。肠道菌群不仅能够直接代谢许多药物,还通过宿主、菌群、药物之间复杂多维的相互作用间接改变药物代谢,从而影响个体对药物治疗的响应(效应、毒性、耐药性等)。肠道菌群结构及代谢功能受多种因素的影响。综述近期肠道菌群代谢药物研究领域的重要进展及研究趋势,以期推进精准治疗,促进药物发现及新的治疗策略的出现。     

Gut microbiota modulates drug pharmacokinetics

Abstract

Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.     

The human gut microbiome – a new and exciting avenue in cardiovascular drug discovery

ABSTRACT

Introduction: Over the past decade, numerous research efforts have identified the gut microbiota as a novel regulator of human metabolic syndrome and cardiovascular disease (CVD). With the elucidation of underlying molecular mechanisms of the gut microbiota and its metabolites, the drug-discovery process of CVD therapeutics might be expedited.

Areas covered: The authors describe the evidence concerning the impact of gut microbiota on metabolic disorders and CVD and summarize the current knowledge of the gut microbial mechanisms that underlie CVD with a focus on microbial metabolites. In addition, they discuss the potential impact of the gut microbiota on the drug efficacy of available cardiometabolic therapeutic agents. Most importantly, the authors review the role of the gut microbiome as a promising source of potential drug targets and novel therapeutics for the development of new treatment modalities for CVD. This review also presents the various effective strategies to investigate the gut microbiome for CVD drug-discovery approaches.

Expert opinion: With the elucidation of its causative role in cardiometabolic disease and atherosclerosis, the human gut microbiome holds promises as a reservoir of novel potential therapeutic targets as well as novel therapeutic agents, paving a new and exciting avenue in cardiovascular drug discovery.     

Impact of gut microbiota on drug metabolism: an update for safe and effective use of drugs

The intestinal mucosa and liver have long been considered as the main sites of drug metabolism, and the contribution of gut microbiota to drug metabolism has been under-estimated. However, it is now generally accepted that the gut microbiota plays an important role in drug metabolism prior to drug absorption or during enterohepatic circulation via various microbial enzymatic reactions in the intestine. Moreover, some drugs are metabolized by gut microbiota to specific metabolite(s) that cannot be formed in the liver. More importantly, the metabolism of drugs by gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding drug metabolism by gut microbiota is critical for explaining changes in the pharmacokinetics of drugs, which may cause significant alterations in drug-induced pharmacodynamics and toxicities. In this review, we describe recent progress with regard to the role of metabolism by gut microbiota in some drug-induced alterations of either pharmacological or toxicological effects to emphasize the clinical importance of gut microbiota for safe and effective use of drugs.     

The metabolic effect of gut microbiota on drugs

Abstract

There are more than 1000 species of microbes reside in the human gut, umbering～10¹⁴ microbes. As the invisible organ of human beings, gut microbiota can usually participate in drug metabolism by producing specific enzymes, such as reductase and hydrolytic enzyme, thus affecting the efficacy, toxicity, and bioavailability of drugs. At least 30 commercially available drugs have been shown to be substrates of gut microbes-derived enzymes, and an increasing number of drugs may have the potential to contact with the distal gut with the help of improved release systems or poor solubility/permeability, more drugs are expected to be found to be metabolized through the gut flora. By collecting examples of intestinal flora participating in the metabolism of synthetic drugs and traditional Chinese medicine components, this article provides a comprehensive reference for future researchers to study drug metabolism by intestinal flora. Noticeably, the composition and quantity of intestinal flora varies among individuals, and can be affected by some drug administration (such as antibiotics) or environmental changes (acute plateau hypoxia). This seems to suggest that intestinal flora could have the potential to be a new drug target to affect the efficacy of drugs which can be metabolized by Intestinal flora. Accordingly, understanding the impact of intestinal flora on drug metabolism and clarifying the drug transformation process is of great significance for guiding rational clinical use, individualized use, toxicological evaluation, and promoting drug discovery and development.     

Metabolomics in pharmacology - a delve into the novel field of pharmacometabolomics

ABSTRACT

Introduction: Pharmacometabolomics is an emerging science pursuing the application of precision medicine. Combining both genetic and environmental factors, the so-called pharmacometabolomic approach guides patient selection and stratification in clinical trials and optimizes personalized drug dosage, improving efficacy and safety.

Areas covered: This review illustrates the progressive introduction of pharmacometabolomics as an innovative solution for enhancing the discovery of novel drugs and improving research and development (R&D) productivity of the pharmaceutical industry. An extended analysis on published pharmacometabolomics studies both in animal models and humans includes results obtained in several areas such as hepatology, gastroenterology, nephrology, neuropsychiatry, oncology, drug addiction, embryonic cells, neonatology, and microbiomics.

Expert opinion: a tailored, individualized therapy based on the optimization of pharmacokinetics and pharmacodynamics, the improvement of drug efficacy, and the abolition of drug toxicity and adverse drug reactions is a key issue in precision medicine. Genetics alone has become insufficient for deciphring intra- and inter-individual variations in drug-response, since they originate both from genetic and environmental factors, including human microbiota composition. The association between pharmacogenomics and pharmacometabolomics may be considered the new strategy for an in-deep knowledge on changes and alterations in human and microbial metabolic pathways due to the action of a drug.     

The influence of the gut microbiota on the bioavailability of oral drugs

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.KEY WORDS: Gut microbiota, Oral drugs, Bioavailability, Probiotics, Colon-specific drug delivery system     

Role of the gut microbiome in cardiovascular drug response: The potential for clinical application

Response to cardiovascular drugs can vary greatly between individuals, and the role of the microbiome in this variability is being increasingly appreciated. Recent evidence indicates that bacteria and other microbes are responsible for direct and indirect effects on drug efficacy and toxicity. Pharmacomicrobiomics aims to uncover variability in drug response due to microbes in the human body, which may alter drug disposition through microbial metabolism, interference by microbial metabolites, or modification of host enzymes. In this review, we present recent advances in our understanding of the interplay between microbes, host metabolism, and cardiovascular drugs. We report numerous cardiovascular drugs with evidence of, or potential for, gut-microbe interactions. However, the effects of gut microbiota on many cardiovascular drugs are yet uninvestigated. Finally, we consider potential clinical applications for the described findings.     

Gut microbiota: what is its place in pharmacology?

ABSTRACT

Introduction: In each section of the human gastrointestinal (GI) tract we may find bacteria that are adapted to local conditions and fulfill an important role in the proper functioning of the body. The gut microorganisms are crucial in human physiology in areas as diverse as the brain and the immune system functions. Therefore, there is a close relationship between the intestinal microbiota, its metabolic activity, and health of the host.

Areas covered: In this review, we explore the host–microbiome interactions and characterize the role they may play in drug metabolism and toxicity. The study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect databases.

Expert opinion: Increasing unhealthy eating habits, stress, antibiotic therapy, unfavorable environmental factors, and genetic predisposition contribute to imbalances in the composition and function of the GI tract microbes and the initiation and progression of disease processes. Restoration of the balanced gut microbiota composition is possible by oral administration of probiotics.     

Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

ABSTRACT

Introduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorial etiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut microbiota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiota modulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.

Areas covered: Published articles including patients with irritable bowel syndrome reporting data about rifaximin activity and safety have been searched throughout the literature and selected.

Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting. Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulating activity. It is effective in inducing symptoms relief in patients with IBS, even after repeated treatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild and infrequent; microbial resistance is rare and transient, due to the high local concentration of the drug and to the absence of horizontal transmission. Clostridium difficile infection is not usual in patients receiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppression, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is an antibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and is not expected to interfere with drug metabolism in patients with normal hepatic function. These properties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.     

Regulation of drug metabolism and toxicity by multiple factors of genetics,epigenetics, lncRNAs,gut microbiota,and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO)

Variations in drug metabolism may alter drug efficacy and cause toxicity; better understanding of the mechanisms and risks shall help to practice precision medicine. At the 21^st International Symposium on Microsomes and Drug Oxidations held in Davis, California, USA, in October 2–6, 2016, a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity, and discussed potential implications to personalized medications. A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption, distribution, metabolism, and excretion (ADME) and drug response. Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented. In addition, the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed. These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.     

The role of gut microbiota in the modulation of drug action: a focus on some clinically significant issues

Introduction: A healthy gut microbiota is necessary for the normal operation of several body functions, including gastrointestinal sensitivity and motility, lipid and glucid metabolism, immune surveillance, and host behavior. In addition, intestinal bacteria contribute to determining the pharmacological properties of several drugs by producing different drug metabolizing enzymes.

Areas covered: Four enzymatic processes are discussed: prodrug activation; drug inactivation; drug deconjugation; and hydrolysis of natural glycosides with further metabolism of released aglycones. For each of these processes, a literature search has been undertaken on certain paradigmatic examples that have significant clinical implications: aminosalicylates and anthranoid laxatives; digoxin; irinotecan and non-steroidal anti-inflammatory drugs (NSAIDs); rutin, diosmin, and baicalin.

Expert commentary: The modulation of certain reactions catalyzed by gut bacterial enzymes may offer new opportunities to improve the clinical efficacy of drugs such as aminosalicylates, and natural glycosides by increasing their metabolic transformation, and of digoxin by reducing its inactivation, or to decrease the lower intestinal toxicity of irinotecan, and NSAIDs by inhibiting the hydrolytic cleavage of their conjugates. Randomized clinical trials are awaited to clarify whether new intervention strategies may modulate these processes and provide clinical benefits such as improved therapeutic outcomes and drug safety profiles.     

Liposomal antibiotics for the treatment of infectious diseases

Introduction: Liposomal delivery systems have been utilized in developing effective therapeutics against cancer and targeting microorganisms in and out of host cells and within biofilm community. The most attractive feature of liposome-based drugs are enhancing therapeutic index of the new or existing drugs while minimizing their adverse effects.

Areas covered: This communication provides an overview on several aspects of liposomal antibiotics including the most widely used preparation techniques for encapsulating different agents and the most important characteristic parameters applied for examining shape, size and stability of the spherical vesicles. In addition, the routes of administration, liposome–cell interactions and host parameters affecting the biodistribution of liposomes are highlighted.

Expert opinion: Liposomes are safe and suitable for delivery of variety of molecules and drugs in biomedical research and medicine. They are known to improve the therapeutic index of encapsulated agents and reduce drug toxicity. Recent studies on liposomal formulation of chemotherapeutic and bioactive agents and their targeted delivery show liposomal antibiotics potential in the treatment of microbial infections.     

The role of probiotics on each component of the metabolic syndrome and other cardiovascular risks

Introduction: Probiotics are defined as live microorganisms that when administered in adequate amounts confer health benefits to the host. The consumption of probiotics has gained increasing recognition from the scientific community due to the promising effects on metabolic health through gut microbiota modulation.

Areas covered: This article presents a review of scientific studies investigating probiotic species and their effects on different risk factors of the metabolic syndrome (MetS). This article also presents a summary of the major mechanisms involved with gut microbiota and the components of the MetS and raises the key issues to be considered by scientists in search of probiotics species for treatment of patients suffering from this metabolic disorder.

Expert opinion: Probiotics may confer numerous health benefits to the host through positive gut microbiota modulation. The strain selection is the most important factor for determining health effects. Further studies may consider gut microbiota as a novel target for prevention and management of MetS components and other cardiovascular risks.     

Insights into gastrointestinal microbiota-generated ginsenoside metabolites and their bioactivities

Abstract

The gastrointestinal microbiota and host co-evolve into a complex ‘super-organism,’ and this relationship plays a vital role in many physiological processes, such as drug metabolism. Ginseng is an important medicinal resource and the main ingredients are ginsenosides, which are less polar, difficult to absorb, and have low bioavailability. However, studies have shown that the biological activity of ginsenosides such as compound K (CK), ginsenoside Rg3 (Rg3), ginsenoside Rh2 (Rh2), 20(S)-protopanaxatriol (20(S)-PPT), and 20(S)-protopanaxadiol (20(S)-PPD) is closely related to the gastrointestinal microbiota. In this paper, the metabolic pathway of gastrointestinal microbiota-generated ginsenosides and the main pharmacological effects of these metabolites are discussed. Furthermore, our study provides a new insight into the discovery of novel drugs. Specifically, in new drug screening process, candidates with low biological activity and bioavailability should not be excluded. Because their metabolites may exhibit good pharmacological effects due to the involvement of the gastrointestinal microbiota. In addition, in further research studies to develop probiotics, a combination of agents could exert greater efficacy than single agents. Moreover, differences in lifestyle and diet lead to differences in the gastrointestinal microbiota in the human body. Therefore, administration of the same drug dose to different individuals could elicit different therapeutic effects, owing to the involvement of the gastrointestinal microbiota. Thus, treatment accuracy could be achieved by detecting the gastrointestinal microbiota before drug treatment.

• Highlights

• Gastrointestinal microbiota plays a decisive role in bioactivities of ginsenosides.

• The metabolic pathway and main pharmacological effects of ginsenoside metabolites are discussed.

• It provides new insights into novel drug discovery and further research to find probiotic, combinations to exert greater efficacy.

• Differences in lifestyle and diet, varies the gastrointestinal microbiota in the human body. However, the same dose of a drug producing different therapeutic effects may involve gastrointestinal microbiota.

     

Mechanisms of gastrointestinal microflora on drug metabolism in clinical practice

Considered as an essential “metabolic organ”, intestinal microbiota plays a key role in human health and the predisposition to diseases. It is an aggregate genome of trillions of microorganisms residing in the human gastrointestinal tract. Since the 20th century, researches have showed that intestinal microbiome possesses a variety of metabolic activities that are able to modulate the fate of more than 30 approved drugs and immune checkpoint inhibitors. These drugs are transformed to bioactive, inactive, or toxic metabolites by microbial direct action or host-microbial co-metabolism. These metabolites are responsible for therapeutic effects exerted by these drugs or side effects induced by these drugs, even for death. In view of the significant effect on the drugs metabolism by the gut microbiota, it is pivotal for personalized medicine to explore additional drugs affected by gut microbiota and their involved strains for further making mechanism clear through suitable animal models. This review mainly focus on specific mechanisms involved, with reference to the current literature about drugs metabolism by related bacteria or its enzymes available.     

药物微生物组学:肠道微生物与个体化用药

药物的安全性与有效性是临床治疗中的关键问题,大量研究表明,人体微生物与药物的疗效、不良反应等显著相关。随着人类微生物组计划的实施,药物微生物组学成为当前生命科学和医学的研究热点。药物微生物组学是药物基因组学的重要扩展和补充,致力于研究药物与微生物之间的相互作用及其与药物效应之间的关系。药物微生物组学研究尚处于起步阶段,其发展将为个体化医学和精准医疗提供必要参考。简介药物微生物组学的发展,并对肠道菌群与个体化用药的国内外研究现状进行综述。     

Siderophores; iron scavengers: the novel & promising targets for pathogen specific antifungal therapy

Introduction: The recent emergence of resistance, toxicity paradigm and limited efficacy of conventional antifungal drugs necessitate the identification of de novo targets in fungal metabolism. One of the most critical physiological processes during in vivo pathogenesis is maintenance of iron homeostasis. The most life threatening opportunistic human fungal pathogens like Aspergillus, Candida and Cryptococcus exploit the siderophore mediated iron uptake mechanism either for survival, virulence, propagation or resistance to oxidative stress envisaged in vivo during infection.

Areas covered: In this review, we will highlight the metabolic pathways; specifically siderophore biosynthesis, uptake and utilisation, triggered in the fungal pathogens in iron starving conditions and the various putative targets viable in these pathways to be recruited as novel therapeutic antidotes either via biosynthetic enzymes catalytic site inhibitors or as drug conjugates through trojan horse approach and further role in the development of fungal specific reliable diagnostic markers.

Expert opinion: Siderophores are the weapons released by a pathogen to conquer the battle for iron acquisition. Hence, the fungal siderophore biosynthetic pathways along with their uptake and utilisation mechanisms represent an ideal target for pathogen specific, host friendly therapeutic strategy which would block the proliferation of parasite without causing any harm to the mammalian host.