Gut microbiota-mediated bile acid metabolism: implications for oral drug absorption

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dc.check.embargoformatEmbargo not applicable (If you have not submitted an e-thesis or do not want to request an embargo)en
dc.check.infoNot applicableen
dc.check.opt-outYesen
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dc.contributor.advisorGahan, Cormac G.en
dc.contributor.advisorJoyce, Susanen
dc.contributor.authorEnright, Elaine F.
dc.contributor.funderIrish Research Councilen
dc.contributor.funderFulbright Associationen
dc.date.accessioned2020-01-16T11:18:09Z
dc.date.available2020-01-16T11:18:09Z
dc.date.issued2019
dc.date.submitted2019
dc.description.abstractIn recent years, it has been elucidated that, in addition to host genetics, the gut microbiome must be considered as a source of pharmacokinetic variability. As newly emerging drug candidates trend toward low solubility and/or permeability, biopharmaceutical properties that prolong gastrointestinal residence time, and thereby microbial contact, identifying and manipulating the microbial processes influencing drug disposition will have fruitful consequences for personalized healthcare. To date, pharmacokinetic research at the host-microbe interface has been primarily focussed on effects on drug metabolism, with minimal consideration to the absorption process (as reviewed in Chapter I). Thus, this thesis investigates a potential mechanism, ‘microbial bile acid metabolism’, by which the intricate interplay between the host and gut bacteria may affect the pre-absorption behaviour and uptake of orally administered drugs. Bile salts have long been appreciated within the pharmaceutical field to be efficient solubilizers of lipophilic drugs. It is also now known that bile salts are important signalling molecules, with the potential to regulate xenobiotic-processing genes via bile acid-activated receptors (BARs). As the size and composition of the bile acid pool is regulated by gut bacterial bile acid metabolism, we propose that inter-individual differences in drug response may be partly attributed to variations in this specific microbial function. In the intestine, host synthesized tauro- or glyco-conjugated bile acids are sequentially deconjugated and 7α-dehydroxylated by microbial enzymes. These biotransformative reactions augment the diversity and alter the physicochemical properties of the bile acid pool. Herein, the effect of bile acid deconjugation and dehydroxylation on bile salt micelle solubilization capacity (Chapter II and III), supersaturated formulation stability (Chapter IV), drug-processing gene expression (Chapter V and VI), as well as passive and active transport mechanisms (Chapter III and V) was investigated. Bile acid conjugation and, in particular, hydroxylation state were determined to significantly influence the phase behaviour of poorly water-soluble drugs (PWSDs). Firstly, dihydroxy bile salt micelles were shown to possess a greater solubilization capacity for PWSDs than trihydroxy counterparts. Dihydroxy bile acids were also observed to be more efficient crystallization inhibitors, and thereby significantly improved the stability of supersaturated solutions of atazanavir, a weakly basic PWSD, relative to trihydroxy species. In addition, the crystallization onset of atazanavir in media designed to mimic a range of representative healthy subject intestinal fluids exhibited a bile salt concentration-dependence, further indicating that gut microbial activity may influence crystallization kinetics in vivo by regulating bile acid pool size. Collectively, these findings suggest that: (1) microbial bile acid metabolism may impact intraluminal drug behaviour, and (2) that close attention should be paid to the concentration and composition of bile salts used in simulated intestinal media when assessing both crystalline and supersaturating formulations to improve in vitro-in vivo predictiveness. This thesis has also illustrated that bile salt conjugation and hydroxylation state can influence the transcription of genes encoding proteins involved in drug disposition. Furthermore, this work identified a novel mechanism by which unconjugated dihydroxy bile acids can affect drug uptake through inhibition of P-glycoprotein ATPase activity. Overall, our research sheds new light on the multitude of mechanisms by which microbial bile acid metabolism may influence the drug absorption process. This effect might be most significant in disease states where gut microbiota alterations are exaggerated.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationEnright, E. F. 2019. Gut microbiota-mediated bile acid metabolism: implications for oral drug absorption. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/9522
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectIrish Research Council (GOIPG/2015/3261)en
dc.relation.projectFulbright (PS00274276)en
dc.rights© 2019, Elaine F. Enright.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectMicrobiotaen
dc.subjectBile acid metabolismen
dc.subjectPharmacokineticsen
dc.subjectBile aciden
dc.subjectMicrobiomeen
dc.subjectDrug absorptionen
dc.thesis.opt-outtrue
dc.titleGut microbiota-mediated bile acid metabolism: implications for oral drug absorptionen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhDen
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