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

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dc.contributor.advisor Gahan, Cormac G. en
dc.contributor.advisor Joyce, Susan en Enright, Elaine F. 2020-01-16T11:18:09Z 2020-01-16T11:18:09Z 2019 2019
dc.identifier.citation Enright, E. F. 2019. Gut microbiota-mediated bile acid metabolism: implications for oral drug absorption. PhD Thesis, University College Cork. en
dc.description.abstract In 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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2019, Elaine F. Enright. en
dc.rights.uri en
dc.subject Microbiota en
dc.subject Bile acid metabolism en
dc.subject Pharmacokinetics en
dc.subject Bile acid en
dc.subject Microbiome en
dc.subject Drug absorption en
dc.title Gut microbiota-mediated bile acid metabolism: implications for oral drug absorption en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD en
dc.internal.availability Full text not available en Not applicable en
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council en
dc.contributor.funder Fulbright Association en
dc.description.status Not peer reviewed en Pharmacy en
dc.check.type No Embargo Required
dc.check.reason Not applicable en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.embargoformat Embargo not applicable (If you have not submitted an e-thesis or do not want to request an embargo) en
dc.internal.conferring Spring 2020 en
dc.internal.ricu APC Microbiome Institute en
dc.relation.project Irish Research Council (GOIPG/2015/3261) en
dc.relation.project Fulbright (PS00274276) en

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© 2019, Elaine F. Enright. Except where otherwise noted, this item's license is described as © 2019, Elaine F. Enright.
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