The Impact of the Gut Microbiota on Drug Metabolism and Clinical Outcome.

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Abstract

The significance of the gut microbiota as a determinant of drug pharmacokinetics and accordingly therapeutic response is of increasing importance with the advent of modern medicines characterised by low solubility and/or permeability, or modified-release. These physicochemical properties and release kinetics prolong drug residence times within the gastrointestinal tract, wherein biotransformation by commensal microbes can occur. As the evidence base in support of this supplementary metabolic "organ" expands, novel opportunities to engineer the microbiota for clinical benefit have emerged. This review provides an overview of microbe-mediated alteration of drug pharmacokinetics, with particular emphasis on studies demonstrating proof of concept in vivo. Additionally, recent advances in modulating the microbiota to improve clinical response to therapeutics are explored.

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Most cited references 37

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Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism.

T. Clayton, D. Baker, J Lindon … (2009)

We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by (1)H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.

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Circadian Disorganization Alters Intestinal Microbiota

Robin Voigt, Christopher Forsyth, Stefan Green … (2014)

Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases.

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The gastrointestinal microbiota as a site for the biotransformation of drugs.

Tiago M. Sousa, Ronnie Paterson, Vanessa Moore … (2008)

There are 100 trillion microbes in the human gastrointestinal tract with numbers increasing distally. These microbiota secrete a diverse array of enzymes (primarily for carbohydrate and protein fermentation) giving them substantial metabolic potential which can have major implications for drug stability. At least thirty drugs which are, or have been, available commercially, were subsequently shown to be substrates for these bacterial enzymes, and with increasing numbers of new and existing drugs having the potential for contact with the distal gut (through modified release systems or poor solubility/permeability), many more are expected to be discovered. The major concern with bacterial drug degradation is the behaviour of the metabolite; is it more or less active than the parent compound, or has toxicity resulted? For example, there were eighteen deaths in 1993 due to a drug interaction in which a toxic drug metabolite was produced by bacterial fermentation. Thus, the objective of this review is the provision of a comprehensive overview of this area; the gastrointestinal microbiota, their drug substrates and metabolic mechanisms, and approaches to studying this further are discussed.

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Journal

Journal ID (iso-abbrev): Yale J Biol Med

Title: The Yale journal of biology and medicine

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ISSN (Electronic): 1551-4056

ISSN (Print): 0044-0086

Publication date (Electronic): September 2016

Volume: 89

Issue: 3

Affiliations

[1 ] APC Microbiome Institute, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland.

[2 ] APC Microbiome Institute, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland.

[3 ] APC Microbiome Institute, University College Cork, Cork, Ireland; School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland.

Article

PMC ID: 5045146

PubMed ID: 27698621

SO-VID: 06ad0a15-c053-43db-a326-2cfdfc0427f7

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Keywords: drug metabolism,gastrointestinal,microbiome,microbiota,pharmacokinetics

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Keywords: drug metabolism, gastrointestinal, microbiome, microbiota, pharmacokinetics

The Impact of the Gut Microbiota on Drug Metabolism and Clinical Outcome.

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Abstract

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Tick microbiome

Most cited references 37

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism.

Circadian Disorganization Alters Intestinal Microbiota

The gastrointestinal microbiota as a site for the biotransformation of drugs.

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