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Review
. 2021 Jul;11(7):1789-1812.
doi: 10.1016/j.apsb.2020.09.013. Epub 2020 Sep 28.

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

Xintong Zhang  1 , Ying Han  1 , Wei Huang  1 , Mingji Jin  1 , Zhonggao Gao  1
Affiliations
Review

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

Xintong Zhang et al. Acta Pharm Sin B. 2021 Jul.

Abstract

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.

Keywords: 5-ASA, 5-aminosalicylic acid; AA, ascorbic acid; ABC, ATP-binding cassette; ACS, amphipathic chitosan derivative; AMI, amiodarone; AQP4, aquaporin 4; AR, azoreductase; ASP, amisulpride; BBR, berberine; BCRP, breast cancer resistance protein; BCS, biopharmaceutics classification system; BDDCS, the biopharmaceutics drug disposition classification system; BDEPT, the bacteria-directed enzyme prodrug therapy; BSH, bile salt hydrolase; Bioavailability; CA, cholic acid; CDCA, chenodeoxycholic acid; CPP, cell-penetrating peptide; CS, chitosan; Colon-specific drug delivery system; DCA, deoxycholic acid; DRPs, digoxin reduction products; EcN, Escherichia coli Nissle 1917; FA, folate; FAO, Food and Agriculture Organization of the United Nations; GCDC, glycochenodeoxycholate; GL, glycyrrhizic acid; Gut microbiota; HFD, high fat diet; HTC, hematocrit; IBD, inflammatory bowel disease; LCA, lithocholic acid; LPS, lipopolysaccharide; MATEs, multidrug and toxin extrusion proteins; MDR1, multidrug resistance gene 1; MDR1a, multidrug resistance protein-1a; MKC, monoketocholic acid; MPA, mycophenolic acid; MRP2, multidrug resistance-associated protein 2; NEC, necrotizing enterocolitis; NMEs, new molecular entities; NRs, nitroreductases; NSAIDs, non-steroidal anti-inflammatory drugs; NaDC, sodium deoxycholate; NaGC, sodium glycholate; OATs, organic anion transporters; OCTNs, organic zwitterion/cation; OCTs, organic cation transporters; Oral drugs; P-gp, P-glycoprotein; PD, Parkinson's disease; PPIs, proton pump inhibitors; PT, pectin; PWSDs, poorly water-soluble drugs; Probiotics; RA, rheumatoid arthritis; RBC, red blood cell; SCFAs, short-chain fatty acids; SGLT-1, sodium-coupled glucose transporter 1; SLC, solute carrier; SLN, solid lipid nanoparticle; SP, sulfapyridine; SSZ, sulfasalazine; SVCT-1/2, the sodium-dependent vitamin C transporter-1/2; T1D, type 1 diabetes; T1DM, type 1 diabetes mellitus; T2D, type 2 diabetes; TCA, taurocholate; TCDC, taurochenodeoxycholate; TDCA, taurodeoxycholate; TLCA, taurolithocholate; TME, the tumor microenvironment; UDC, ursodeoxycholic acid; WHO, World Health Organization; an OTC drug, an over-the-counter drug; cgr operon, cardiac glycoside reductase operon; dhBBR, dihydroberberine; pKa, dissociation constant; the GI tract, the gastrointestinal tract.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Image 1
Graphical abstract
Figure 1
Figure 1
The effects of the gut microbial enzyme activity on the first-pass effect and the enterohepatic recirculation. After being administered orally, some of the drugs can be metabolized by microbial enzymes before absorption. Then the drugs and metabolites can be transported to the liver via the portal vein. In the liver, some of the drugs may go through the oxidation and conjugation caused by hepatic enzymes. After that, drugs and/or their metabolites can enter the systemic circulation or be delivered back to the intestine where they can be reactivated by some microbial enzymes or enzymes in the gut and transported to the liver again. Both the first-pass effect and the enterohepatic recirculation can influence the bioavailability of oral drugs.
Figure 2
Figure 2
Four biopharmaceutics drug disposition classification system (BDDCS) classifications of oral drugs and the prediction of the metabolizing enzyme and transporter effects by BDDCS.
Figure 3
Figure 3
The metabolism of bile acids modulated by BSHs and 7α-dehydroxylases. The conjugated primary bile acids are released in the duodenum to facilitate the digestion and then can be converted to free primary bile acids, CA and CDCA, by BSHs in the terminal ileum and colon. These unconjugated primary bile acids are then biotransformed into secondary bile acids after 7α-dehydroxylation by 7α-dehydroxylases in the colon. CA, cholic acid; CDCA, chenodeoxycholic acid.
Figure 4
Figure 4
Schematic illustration of the effects of the gut microbial 7α-dehydroxylase activity on the solubilization capacity of bile salt micelles for poorly water-soluble drugs investigated in vitro. Reprinted with the permission from Ref.. Copyright © 2017 American Chemical Society.
Figure 5
Figure 5
Schematic illustration of the effects of deconjugated bile acids generated by BSHs on the inhibition of the P-gp ATPase. Reprinted with the permission from Ref.. Copyright © 2018 American Chemical Society.
Figure 6
Figure 6
Schematic illustration of the principle of colon-targeted delivery system (CODES™) technology. There are three main parts of the system. Lactulose and the active drug are contained in the inner core, which is coated with a layer of acid soluble material, and then further coated with another layer of enteric material. The enteric coating protects the tablet while it is in the stomach and then dissolves when the tablet reaches the small intestine. Because of the acid-soluble polymer coating, the drug could not release from the tablet, while gastrointestinal fluids can penetrate through the coating layer to dissolve the lactulose. After reaching the colon, the gut microbiota can degrade lactulose diffusing through the coating to produce organic acids. This process results in a lower pH of the local environment which leads to the dissolution of the acid-soluble coating and the release of the drug.
Figure 7
Figure 7
Possible relationships between the gut microbiota and oral drugs' bioavailability.
See this image and copyright information in PMC

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