Pharmacological Efficacy/Toxicity of Drugs: A Comprehensive Update About the Dynamic Interplay of Microbes

Abstract

Oral ingestion is a common, easy to access, route for therapeutic drugs to be delivered. The conception of the gastrointestinal tract as a passive physiological compartment has evolved toward a dynamic perspective of the same. Thus, microbiota plays an important role in contributing with additional metabolic capacities to its host as well as to its phenotypic heterogeneity. These adaptations in turn influence the efficacy and toxicity of a broad range of drugs. Notwithstanding, xenobiotics and therapeutic drugs affecting the microbiome's activity also significantly impact metabolism affecting different organs and tissues, and thereby drugs' toxicity/efficacy effects. Other physiological interfaces (i.e., gut, lungs, and skin) also represent complex media with features about microbiota's composition. In addition, there have been described key regulatory effects of microbes on immunotherapy, because of its potential harnessing the host immune system, mental disorders by modulating neuroendocrine systems and cancer. These alterations are responsible of physiological variations in the response(s) between individuals and populations. However, the study of population-based differences in intestinal microbial-related drug metabolism has been largely inferential. This review outlines major reciprocal implications between drugs and microbes regulatory capacities in pharmacotherapy.

Keywords: Efficacy; Metabolism; Microbes; Therapeutics; Toxicity.

Figure 1.

Microbial-mediated biotransformation processes influencing drug disposition.

Figure 2.

Examples of drugs susceptible of microbial-mediated biotransformation.

Figure 3.

Interactions of gut microbiota with therapeutic drugs. The black dotted arrow represented the absorption process of drugs. The bold grey arrow represented a schematic interaction of the gut microbiota with the immune-metabolic axis and the different mechanisms proposed to explain its implication in toxicity efficacy and health/disease risk. Mechanisms underlying the connection of drugs-induced host detoxifying metabolism activation influenced by gut microbiota (e.g. multidrug resistance protein, MDRs; the cytochrome P450 superfamily, CYPs; and the ATP-binding cassett transporters, ABC transporters) and microbiota biotransformations (e.g. hydrolysis, dehydroxylation, denitration, amine formation and proteolysis). Drugs metabolism occurs associated to the energetic cell metabolism; and the endocannabinoid system (eCB) participates in the regulation of energy homeostasis and gut permeability (increasing the possibility to appears a metabolic endotoxemia). The deregulation of cellular energetic metabolism could impair the activation of ABC transporters causing together inflammation (cytokines production) and alterations in gut permeability increasing the toxic effects.