Sofia Cussotto1, Jacinta Walsh2, Anna V Golubeva1, Alexander V Zhdanov3, Conall R Strain4, Fiona Fouhy4, Catherine Stanton5, Timothy G Dinan6, Niall P Hyland7, Gerard Clarke6, John F Cryan8, Brendan T Griffin9. 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: j.cryan@ucc.ie. 9. APC Microbiome Ireland, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland. Electronic address: brendan.griffin@ucc.ie.
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. 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).
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).
Authors: John R Kelly; Claire M Gillan; Jack Prenderville; Clare Kelly; Andrew Harkin; Gerard Clarke; Veronica O'Keane Journal: Front Psychiatry Date: 2021-12-17 Impact factor: 4.157
Authors: Tao Yang; Xue Mei; Ethel Tackie-Yarboi; Millicent Tambari Akere; Jun Kyoung; Blair Mell; Ji-Youn Yeo; Xi Cheng; Jasenka Zubcevic; Elaine M Richards; Carl J Pepine; Mohan K Raizada; Isaac T Schiefer; Bina Joe Journal: Hypertension Date: 2022-05-10 Impact factor: 9.897