Pharmacokinetics

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  • Gastrointestinal microbiome

    • Gastrointestinal Microbiome and Pharmacology

    • Gastrointestinal microbiome consists of bacteria, viruses, fungi and microbial eukaryotes.15 

    • Greater than 90% of the gut microbiota are described by members of two bacteria phyla, Bacteroidetes and Firmicutes.

    • Bacterioides biacutis

      • "Bacterioides biacutis-one of many commensal anaerobic Bacteroides species in the gastrointestinal tract-cultured and blood agar medium for 48 hours.

      • "The phylum Bacteroidetes consists of 3 large classes of Gram-negative, nonsporeforming, anaerobic or aerobic and rod-shaped bacteria."15

      • Image obtained from the CDC Public Health Image Library (https://phil.cdc.gov/default.aspx)

      • Attribution:  US gov, Public Domain via Wikimedia Commons

      • https://commons.wikimedia.org/wiki/File:Bacteroides_biacutis_01.jpg

       

       

    • Bacillus subtilis (Firmicutes/Bacillota)

  • The gut microbiomes is described by over 1000 distinct species with substantial differences between individuals.15 

 

  • The challenge that physicians face in diagnostics and therapeutics is driven by the recognition that phenotypes are not defined solely on the basis of genes alone but rather on interactions between genes and gene products and further by the interactions between genetics and environmental factors.16 

  • For example, epigenetic influences gene expression despite cells having the same DNA sequences.

    • Epigenetic-induced changes appear associated with a number of disease processes.16 

  • Proteomics describes relationships between large numbers of cellular proteins and disease.

    • These interactions allow enhancement of cellular biological potentialities beyond the 23,000 human genes in the genome by means of posttranslational processing, alternate splicing, and posttranslational modifications map to many unique and therapeutically relevant consequences.16

    Microbiomics emphasize the relationship between resident human microbes and their relationship to human health.

    • The significance of such interactions is suggested by the number of genes in the human haploid genome (about 23,000) compared to the 3-4 million genes associated with resident microbes in humans.

  • Maturation of the immune system, along with metabolic balance, disease susceptibility and brain function appear to be influenced by those microbes associated with skin surfaces and human mucosal surfaces.16 

     

    • "Human Gut Microbes Metabolize Xenobiotics"

      • "The microorganisms that inhabit the human gut alter the chemical structures of ingested compounds, including dietary components, industrial  chemicals, and drugs.

      • "These changes affect xenobiotic toxicity, biological activity, and bioavailability.

      • "The gut microbial enzymes responsible for many of these transformations are poorly understood. Me, methyl."

      • Attribution: Koppel N, et al. Chemical transformation of xenobiotics by the human gut microbiota. Science, 2017, 356 (6344): eaag2770. https://www.science.org/doi/10.1126/science.aag2770.

     

     

  • The Microbiome and Disease

    • The microbiome seems to be involved in a number of human diseases, although the underlying mechanism remains to be elucidated.15  

      • Diseases in which microbiome have been implicated includes:

        1. Autoimmune diseases

        2. Autism

        3. Hepatic disease

        4. Cancer

        5. Cardiovascular Disease.

      • About 16% of all cancers in the United States appear closely related to elements of the microbiome. 15 

        • Microbiome elements likely associated with cancer.:

          • hepatitis C

          • Heliobacter pylori

          • Human papilloma virus.

      • DNA cleavage and potentially associated colorectal cancer may result from colibactin-producing Escherichia coli.15 

        • Colibactin is considered a secondary metabolite associated with certain bacterial strains present in the human gut.17 

        • Colibactin-producing bacteria appear correlated with human colorectal cancer.

        • Colibactin exhibits a heterodimeric structure with two DNA-reactive residues allowing formation of interstrand adenine cross-links (alkylation) between opposing DNA strands.17 

        • Colibactin + E. coli → Colibactin-DNA Cross-link17 


           

 

  • Interactions Between the Microbiome and Drugs

    • Drugs and their Interactions with the Bodies' Microbiome

      • Variation in an individual's response to a drug is affected by the gut microbiome.

      • The microbiome can influence almost every aspect of a drugs interaction in the body.

        • For example, the microbiome can affect:

          • Metabolism of Xenobiotics

          • Influence drug metabolism by modulating phase I (P450 drug metabolizing system) enzymes

            •  and phase II (e.g. conjugation reactions)

          • Influencing drug transporters

          • Affecting enterohepatic circulation Involvement in drug-pharmacodynamic interactions.15,17,18 

      • Gut bacteria can participate in direct drug metabolism.

      • For example, digitoxin, a cardiac glycoside, can be inactivated by the microbe Eggerthella lenta and such inactivation could be important given that variability in drug concentration is especially important if the drug exhibits a narrow therapeutic index.

      • Another example of a narrow therapeutic range agent, tacrolimus appears linked to Faecalibacterium prausnitzii in that patients (kidney transplant) requiring higher tacrolimus doses also exhibited elevated amounts of Faecalibacterium prausnitzii.15,18

      • An example in which microbiome gut bacteria enzymic activity is required for drug activation is illustrated by the prodrug sulfasalazine.

        • Prodrugs are defined as drugs that in their ingested form are not biologically active but upon metabolic transformation a pharmacologically active form results.

        • In this instance the azo bond of sulfasalazine is reduced by gut bacteria yielding the active form, 5-aminosalicylate (mesalamine).


         

Updated June 2025
 

 

 

 

References

  1. Maher TJ Kiel D Chapter 6 G-Protein-Coupled Receptors in Foye's Principles of Medicinal Chemistry (Roche VF Zito SW Lemke TL Williams DA, eds) 8e Wolters Kluwer 2020.

  2. Alenghat FJ Golan DE Chapter 1 Drug-Receptor Interactions in Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy (Golan DE Armstrons EJ Armstong AW, eds) 4e Wolters Kluwer 2017.

  3. von Zastrow M Chapter 2  Drug Receptors & Pharmacodynamics in Basic & Clinical Pharmacology ( Katzung BG Vanderah TW, eds) 14e McGraw Hill 2021.

  4. Flood P Shafer SL Chapter 2 Basic principles of Pharmacology in Stoelting's Pharmacology & Physiology Anesthetic Practice (Flood P Rathmell JP Urman RD, eds) 6e 2022.

  5. Manning DR Blumenthal DK Chapter 3 Pharmacodynamics:  Molecular Mechanisms of Drug Action in Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton LL Knollmann BC, eds) 14e McGraw-Hill 2023.

  6. Burchum JR Rosenthal LD Charles C Chapter 5 Pharmacodynamics Lehne's Pharmacology for Nursing Care 11e Elsevier 2022.

  7. Katzung, BG Introduction:  Chapter 1 The Nature of Drugs & Drug Development & Regulation in Basic and Clinical Pharmacology (Katzung BG Vanderah TW, eds) 15e McGraw Hill 2021.

  8. Geroge Jr AL Neilson EG Chapter 309 Cell Biology and Physiology of the Kidney in Harrison's Principles of Internal Medicine (Loscalzo J Kasper DL Longo DL Fauci AS Hauser SLs Jameson JL, eds) 21e 2022.

  9. Burchum JR Rosenthal LD Charles C Chapter 4 Pharmacokinetics Lehne's Pharmacology for Nursing Care 11e Elsevier 2022.

  10. Singer SJ Nicolson GL The Fluid Mosaic Model of the Structure of Cell Membranes. Science 1972 Feb 18; 175(4023):  720-731.

  11. Watson H Biological membranes Essays Biochem (2015) 59, 43-70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626904/pdf/bse0590043.pdf

  12. Holford NHG Chapter 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action in Basic and Clinical Pharmacology (Katzung BG Vanderah TW, eds) 15e McGraw Hill 2021.

  13. Buxton ILO Chapter 2 Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination in Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton LL Knollmann BC, eds) 14e McGraw-Hill 2023.

  14. Baca QJ Golan DE Chapter 3 Pharmacokinetics  in Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy (Golan DE Armstrons EJ Armstong AW, eds) 4e Wolters Kluwer 2017.

  15. Tsunoda SM Dorrestein PC Knight Rob Chapter 6 The Gastrointestinal Microbiome and Drug Response in Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton LL Knollmann BC, eds) 14e McGraw-Hill 2023.

  16. The Editors Chapter 1 The Practice of Medicine in  in Harrison's Principles of Internal Medicine (Loscalzo J Kasper DL Longo DL Fauci AS Hauser SLs Jameson JL, eds) 21e 2022.

  17. Lam KN Slexander M Turnbaugh PJ Precision Medicine Goes Microscoptic:  Engineering the Microbiome to Improve Drug Outcomes.  Cell Host & Microbe July 10, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709864/

  18. Tsunoda SM Gonzales C Jarmujsch AK Momper JD Ma JD Contribution of the Gut Microbiome to Drug Disposition, Pharmcokinetic and Pharmacodynamic Variability.  Clinical Pharmacokinetics (2021) 60:  971-984. https://link.springer.com/article/10.1007/s40262-021-01032-y

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