The gut microbiome influences the bioavailability of olanzapine in rats
eBioMedicine. 2021-04-01; 66: 103307
DOI: 10.1016/j.ebiom.2021.103307
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1. EBioMedicine. 2021 Apr;66:103307. doi: 10.1016/j.ebiom.2021.103307. Epub 2021
Apr 2.
The gut microbiome influences the bioavailability of olanzapine in rats.
Cussotto S(1), Walsh J(2), Golubeva AV(1), Zhdanov AV(3), Strain CR(4), Fouhy
F(4), Stanton C(5), Dinan TG(6), Hyland NP(7), Clarke G(6), Cryan JF(8), Griffin
BT(9).
Author information:
(1)APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of
Anatomy and Neuroscience, University College Cork, Cork, Ireland.
(2)APC Microbiome Ireland, University College Cork, Cork, Ireland; School of
Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland.
(3)School of Biochemistry and Cell Biology, University College Cork, Cork,
Ireland.
(4)APC Microbiome Ireland, University College Cork, Cork, Ireland; Teagasc Food
Research Centre, Moorepark, Fermoy, County, Cork, Ireland.
(5)APC Microbiome Ireland, University College Cork, Cork, Ireland; Teagasc Food
Research Centre, Moorepark, Fermoy, County, Cork, Ireland; Department of
Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
(6)APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of
Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
(7)APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of
Physiology, University College Cork, Cork, Ireland.
(8)APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of
Anatomy and Neuroscience, University College Cork, Cork, Ireland. Electronic
address: .
(9)APC Microbiome Ireland, University College Cork, Cork, Ireland; School of
Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland.
Electronic address: .
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.
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).
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ebiom.2021.103307
PMCID: PMC8047500
PMID: 33819741 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest BTG has spoken
at events sponsored by AbbVie. CS receives funding from 4D Pharma, Dupont and
Nutricia. GC has spoken at events sponsored by Janssen Ireland and Probi, and
receives funding from Pharmavite. JFC has spoken at events sponsored by Janssen
Ireland, Neuropharmex, Mead Johnson, Friesland Campina, has been a consultant
for Nestle & Alkermes and receives funding from Mead Johnson, Cremo, 4D Pharma,
Dupont, GSK, Suntory Wellness, Pharmavite, and Nutricia. NPH has spoken at
events sponsored by Johnson & Johnson and Coloplast. TGD has spoken at events
sponsored by Servier, Lundbeck, Janssen, AstraZeneca and receives funding from
Mead Johnson, Cremo, 4D Pharma, Dupont, GSK, Suntory Wellness, Pharmavite, and
Nutricia.