dc.contributor.author	Cussotto, Sofia
dc.contributor.author	Walsh, Jacinta
dc.contributor.author	Golubeva, Anna V.
dc.contributor.author	Zhdanov, Alexander V.
dc.contributor.author	Strain, Conall R.
dc.contributor.author	Fouhy, Fiona
dc.contributor.author	Stanton, Catherine
dc.contributor.author	Dinan, Timothy G.
dc.contributor.author	Hyland, Niall P.
dc.contributor.author	Clarke, Gerard
dc.contributor.author	Cryan, John F.
dc.contributor.author	Griffin, Brendan T.
dc.contributor.funder	Yakult Bio-Science Foundation	en
dc.date.accessioned	2021-10-06T11:49:04Z
dc.date.available	2021-10-06T11:49:04Z
dc.date.issued	2021-04-02
dc.date.updated	2021-10-06T11:20:25Z
dc.description.abstract	Background: 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.	en
dc.description.sponsorship	Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).	en
dc.description.status	Peer reviewed	en
dc.description.version	Published Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.articleid	103307	en
dc.identifier.citation	Cussotto, S., Walsh, J., Golubeva, A. V., Zhdanov, A. V., Strain, C. R., Fouhy, F., Stanton, C., Dinan, T. G., Hyland, N. P., Clarke, G., Cryan, J. F. and Griffin, B. T. (2021) 'The gut microbiome influences the bioavailability of olanzapine in rats', EBioMedicine, 66, 103307 (14 pp). doi: 10.1016/j.ebiom.2021.103307	en
dc.identifier.doi	10.1016/j.ebiom.2021.103307	en
dc.identifier.endpage	14	en
dc.identifier.issn	2352-3964
dc.identifier.journaltitle	Ebiomedicine	en
dc.identifier.startpage	1	en
dc.identifier.uri	https://hdl.handle.net/10468/12057
dc.identifier.volume	66	en
dc.language.iso	en	en
dc.publisher	Elsevier	en
dc.relation.project	info:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/	en
dc.relation.uri	https://www.sciencedirect.com/science/article/pii/S2352396421001006
dc.rights	© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)	en
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	en
dc.subject	Antipsychotic	en
dc.subject	Microbiome	en
dc.subject	Pharmacokinetics	en
dc.subject	Diversity	en
dc.subject	Bioavailability	en
dc.subject	CYP	en
dc.title	The gut microbiome influences the bioavailability of olanzapine in rats.	en
dc.type	Article (peer-reviewed)	en

The gut microbiome influences the bioavailability of olanzapine in rats.

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