APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
APC Microbiome Ireland, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland.
EBioMedicine. 2021 Apr;66:103307. doi: 10.1016/j.ebiom.2021.103307. Epub 2021 Apr 2.
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.
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.
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.
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.
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).
肠道微生物群在药物的生物转化中的作用最近受到了关注。目前尚不清楚肠道微生物群是否直接影响口服给药后药物的吸收程度，从而潜在地改变临床药代动力学。
在这项研究中，我们评估了雄性 Sprague Dawley 大鼠的肠道微生物群因抗生素或益生菌给药而发生变化是否会影响两种常用抗精神病药（奥氮平和利培酮）的口服生物利用度。
抗生素诱导的肠道微生物群耗竭使奥氮平的生物利用度显著增加（1.8 倍），而利培酮的生物利用度则不变。肠道微生物群耗竭对参与两种药物代谢的主要 CYP450 酶的表达没有直接影响。然而，十二指肠中的 UGT1A3 表达显著下调。在抗生素给药期间和之后观察到的粪便酶活性降低并没有改变奥氮平和利培酮的离体代谢。在奥氮平的 AUC 与 Alistipes 的相对丰度之间存在显著相关性，但与利培酮无关。
Alistipes 可能在奥氮平药代动力学观察到的改变中起作用。肠道微生物群可能是决定口服给予奥氮平的全身生物利用度的重要变量。需要进一步研究探索肠道微生物群对奥氮平在人类临床药代动力学中的潜在影响。
这项研究得到了 APC Microbiome Ireland 的支持，该研究中心由科学基金会爱尔兰（SFI）通过爱尔兰政府的国家发展计划（拨款号 12/RC/2273 P2）资助，并得到了 Nature Research-Yakult（全球肠道健康赠款；编号 626891）的资助。
