The interest on the role of gut microbiota in the biotransformation of drugs and xenobiotics has grown over the last decades and a deeper understanding of the mutual interactions is expected to help future improvements in the fields of drug development, toxicological risk assessment and precision medicine. In this paper, a microbiome drug metabolism case is presented, involving a lipophilic small molecule, N-(3β-hydroxy-Δ5-cholen-24-oyl)-l-tryptophan, UniPR1331, active as antagonist of the Eph-ephrin system and effective in vivo in a murine orthotopic model of glioblastoma multiforme (GBM). Following the administration of a single 30 mg/kg dose (p.o.) to mice, maximal plasma levels were reached 30 min after dosing and rapidly declined thereafter. To explain the observed in vivo behaviour, in vitro phase I and II metabolism assays were conducted employing mouse and human liver subcellular fractions and profiling main metabolites by means of tandem (HPLC-ESI-MS/MS) and high resolution mass spectrometry (HPLC-ESI-HR-MS). In the presence of in vitro mouse liver fractions, UniPR1331 showed a low phase I metabolic clearance, despite the identification of a 3-oxo and several hydroxylated metabolites. Conversely, after oral administration of UniPR1331 to mice, a novel isobaric metabolite was detected that (i) was subjected, as parent UniPR1331, to enterohepatic circulation (ii) had not been previously identified in vitro in mouse liver microsomes and (iii) was not observed forming after intraperitoneal (i.p.) administration of UniPR1331. An in vitro faecal fermentation assay produced the same chemical entity supporting a major role of gut microbiota in the in vivo clearance of UniPR1331.

中文翻译：

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药物肠道微生物群代谢相互作用：在小鼠中，Eph-ephrin系统的选择性拮抗剂UniPR1331。

在过去的几十年中，人们对肠道菌群在药物和异种生物的生物转化中的作用的兴趣不断增长，对相互作用的深入了解有望帮助药物开发，毒理学风险评估和精密医学领域的未来发展。在本文中，提出了一个微生物组药物代谢病例，涉及一个亲脂性小分子N-（3β-羟基-Δ5-胆碱-24-oyl）-1-色氨酸UniPR1331，它具有作为Eph-ephrin系统拮抗剂的活性，并且在多形性胶质母细胞瘤（GBM）的小鼠原位模型中具有体内有效作用。在给小鼠施用单次30 mg / kg剂量（po）后，给药后30分钟达到最大血浆水平，此后迅速下降。为了解释观察到的体内行为，使用小鼠和人类肝脏亚细胞级分，并通过串联（HPLC-ESI-MS / MS）和高分辨率质谱（HPLC-ESI-HR-MS）对主要代谢产物进行了体外I和II期代谢测定。尽管存在3-氧代和几种羟基化代谢产物，但在体外小鼠肝组分存在下，UniPR1331仍显示出低的I期代谢清除率。相反，将UniPR1331口服给予小鼠后，发现了一种新的等压代谢物，即（i）作为母体UniPR1331经历了肝肠循环（ii）先前尚未在小鼠肝微粒体中进行体外鉴定，而（iii）并未观察到腹膜内（ip）施用UniPR1331后形成。