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dc.contributor.authorCussotto, Sofia
dc.contributor.authorWalsh, Jacinta
dc.contributor.authorGolubeva, Anna V.
dc.contributor.authorZhdanov, Alexander V.
dc.contributor.authorStrain, Conall R.
dc.contributor.authorFouhy, Fiona
dc.contributor.authorStanton, Catherine
dc.contributor.authorDinan, Timothy G.
dc.contributor.authorHyland, Niall P.
dc.contributor.authorClarke, Gerard
dc.contributor.authorCryan, John F.
dc.contributor.authorGriffin, Brendan T.
dc.date.accessioned2021-08-16T11:54:47Z
dc.date.available2021-08-16T11:54:47Z
dc.date.issued2021-04-02
dc.identifier.citationSofia Cussotto, Jacinta Walsh, Anna V. Golubeva, Alexander V. Zhdanov, Conall R. Strain, Fiona Fouhy, Catherine Stanton, Timothy G. Dinan, Niall P. Hyland, Gerard Clarke, John F. Cryan, Brendan T. Griffin, The gut microbiome influences the bioavailability of olanzapine in rats, EBioMedicine, 2021, 66, 103307,. DOI: https://doi.org/10.1016/j.ebiom.2021.103307en_US
dc.identifier.issn2352-3964
dc.identifier.urihttp://hdl.handle.net/11019/2567
dc.descriptionpeer-revieweden_US
dc.description.abstractBackground The role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics. Methods In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone. Findings The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone. Interpretation Alistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted. Funding This research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).en_US
dc.description.sponsorshipScience Foundation Ireland
dc.language.isoenen_US
dc.publisherThe Lanceten_US
dc.relation.ispartofseriesEBioMedicine;66
dc.rights© 2021 The Author(s). Published by Elsevier B.V.*
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttps://www.elsevier.com/tdm/userlicense/1.0/*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectAntipsychoticen_US
dc.subjectMicrobiomeen_US
dc.subjectPharmacokineticsen_US
dc.subjectDiversityen_US
dc.subjectBioavailabilityen_US
dc.subjectCYPen_US
dc.titleThe gut microbiome influences the bioavailability of olanzapine in ratsen_US
dc.typeArticleen_US
dc.identifier.doihttps://doi.org/10.1016/j.ebiom.2021.103307
dc.identifier.piiS2352396421001006
dc.contributor.sponsorScience Foundation Irelanden_US
dc.contributor.sponsorGrantNumber12/RC/2273 P2en_US
dc.source.volume66
dc.source.beginpage103307
refterms.dateFOA2021-08-16T11:54:48Z
dc.source.journaltitleEBioMedicine


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