Hyaluronan (HA) is an extracellular matrix glycosaminoglycan, with important roles in chronic inflammation, cancer and autoimmunity. 4-methylumbelliferone (4-MU), a small molecule inhibitor of HA synthases, is widely used to study HAs interactions with the surrounding tissues and the immune cells. There is substantial experimental and therapeutic interest in using oral 4-MU to inhibit HA synthesis, but pharmacokinetic and pharmacodynamic data on treatment routes have been lacking. Moreover, it recently became clear that the main metabolite of 4-MU, 4-methlyumbelliferyl glucuronide (4-MUG), is bioactive. We therefore sought to define the pharmacokinetics and pharmacodynamics of 4-MU and its active metabolite 4-MUG in mice. Single dose mouse studies showed that 4-MU administered intravenously (i.v.) resulted in 100-fold higher 4-MU exposure compared to oral (p.o.) administration. The 4-MU ratio AUC i.v./AUC p.o. was 96/1. 4-MUG exposures were much higher than 4-MU exposures after both 4-MU i.v. and p.o. administration, but only small differences in 4-MUG exposure were seen after 4-MU i.v. versus p.o. administration. The 4-MUG metabolite was also administered as a single dose both i.v. and p.o. and showed a 25.9% bioavailability. Compared to 4-MUG p.o. dosing, 1.14 higher 4-MUG exposures were seen after 4-MU p.o. dosing. 4-MU exposure after 4-MUG p.o. administration was minimal but similar to 4-MU exposure after 4-MU p.o. administration. In mice treated for several weeks with 4-MU in chow, the 4-MU concentration immediately drops after treatment was stopped, whereas the 4-MUG concentration showed a peak 1 hour after treatment stop. In a build-up study, 4-MU and 4-MUG treatment in mice lead to a plateau of 4-MU concentration starting at 4 days post treatment start. These 4-MU and 4-MUG concentration findings in vivo will inform future clinical studies and experimental work with 4-MU.

中文翻译：

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4-甲基伞形酮及其葡萄糖苷酸代谢物在小鼠体内的药代动力学和药效学

透明质酸 (HA) 是一种细胞外基质糖胺聚糖，在慢性炎症、癌症和自身免疫中具有重要作用。4-甲基伞形酮 (4-MU) 是一种 HA 合成酶的小分子抑制剂，广泛用于研究 HA 与周围组织和免疫细胞的相互作用。使用口服 4-MU 抑制 HA 合成具有实质性的实验和治疗兴趣，但一直缺乏治疗途径的药代动力学和药效学数据。此外，最近发现 4-MU 的主要代谢物 4-methlyumbelliferyl glucuronide (4-MUG) 具有生物活性。因此，我们试图确定 4-MU 及其活性代谢物 4-MUG 在小鼠体内的药代动力学和药效学。单剂量小鼠研究表明，4-MU 静脉内给药（iv ) 与口服 (po) 给药相比，4-MU 暴露量高出 100 倍。4-MU比率AUC iv/AUC po为96/1。4-MU iv 和 po 给药后 4-MUG 的暴露量远高于 4-MU 的暴露量，但 4-MU iv 与 po 给药后 4-MUG 暴露量的差异很小。4-MUG 代谢物也以单剂量 iv 和 po 给药，显示出 25.9% 的生物利用度。与 4-MUG 口服给药相比，4-MUG 口服给药后 4-MUG 暴露量增加了 1.14。4-MUG po 给药后的 4-MU 暴露是最小的，但与 4-MU po 给药后的 4-MU 暴露相似。在食物中用 4-MU 治疗数周的小鼠中，4-MU 浓度在治疗停止后立即下降，而 4-MUG 浓度在治疗停止后 1 小时出现峰值。在一项累积研究中，小鼠的 4-MU 和 4-MUG 治疗导致 4-MU 浓度在治疗开始后 4 天开始出现平台期。这些 4-MU 和 4-MUG 浓度结果in vivo将为未来的 4-MU 临床研究和实验工作提供信息。