UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Department of Chemistry - BMC, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
Eur J Pharm Sci. 2024 Dec 1;203:106922. doi: 10.1016/j.ejps.2024.106922. Epub 2024 Oct 3.
The gut microbiome can metabolise hundreds of drugs, potentially affecting their bioavailability and pharmacological effect. As most gut bacteria reside in the colon, drugs that reach the colon in significant proportions may be most impacted by microbiome metabolism. In this study the anti-colorectal cancer drug trifluridine was used as a model drug for characterising metabolism by the colonic microbiota, identifying correlations between bacterial species and individuals' rates of microbiome drug inactivation, and developing strategies to prevent drug inactivation following targeted colonic delivery. High performance liquid chromatography and ultra-high performance liquid chromatography coupled with high resolution tandem mass spectrometry demonstrated trifluridine's variable and multi-route metabolism by the faecal microbiota sourced from six healthy humans. Here, four drug metabolites were linked to the microbiome for the first time. Metagenomic sequencing of the human microbiota samples revealed their composition, which facilitated prediction of individual donors' microbial trifluridine inactivation. Notably, the abundance of Clostridium perfringens strongly correlated with the extent of trifluridine inactivation by microbiota samples after 2 hours (R = 0.8966). Finally, several strategies were trialled for the prevention of microbial trifluridine metabolism. It was shown that uridine, a safe and well-tolerated molecule, significantly reduced the microbiota's metabolism of trifluridine by acting as a competitive enzyme inhibitor. Further, uridine was found to provide prebiotic effects. The findings in this study greatly expand knowledge on trifluridine's interactions with the gut microbiome and provide valuable insights for investigating the microbiome metabolism of other drugs. The results demonstrate how protection strategies could enhance the colonic stability of microbiome-sensitive drugs.
肠道微生物组可以代谢数百种药物，可能会影响其生物利用度和药理作用。由于大多数肠道细菌都存在于结肠中，因此到达结肠的药物可能会受到微生物组代谢的最大影响。在这项研究中，抗结直肠癌药物三氟尿苷被用作模型药物，用于表征结肠微生物群的代谢，确定细菌种类与个体微生物群药物失活率之间的相关性，并开发在靶向结肠给药后防止药物失活的策略。高效液相色谱和超高效液相色谱与高分辨率串联质谱联用，证明了三氟尿苷在来自 6 名健康人的粪便微生物群中的可变和多途径代谢。在这里，首次将四种药物代谢物与微生物组联系起来。人类微生物群样本的宏基因组测序揭示了它们的组成，这有助于预测个体供体微生物三氟尿苷失活。值得注意的是，产气荚膜梭菌的丰度与微生物群样本在 2 小时后对三氟尿苷失活的程度呈强相关性（R = 0.8966）。最后，尝试了几种预防微生物三氟尿苷代谢的策略。结果表明，尿苷作为一种竞争性酶抑制剂，可显著减少微生物对三氟尿苷的代谢，尿苷是一种安全且耐受良好的分子。此外，还发现尿苷具有益生元作用。本研究的结果极大地扩展了三氟尿苷与肠道微生物组相互作用的知识，并为研究其他药物的微生物组代谢提供了有价值的见解。研究结果表明，保护策略如何增强对微生物群敏感药物的结肠稳定性。
