Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, Utah 84112; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112.
College of Pharmacy, Roseman University of Health Sciences, South Jordan, Utah 84095.
J Pharm Sci. 2018 Sep;107(9):2472-2478. doi: 10.1016/j.xphs.2018.05.005. Epub 2018 May 22.
Ro 25-6981 is a highly potent and selective blocker of N-methyl-d-aspartate receptors that has been shown to possess both rapid and sustained antidepressant activity. In the present study, we report the biopharmaceutical characterization of Ro 25-6981 by evaluating gastrointestinal stability, transepithelial permeability, stability in human liver microsomes, and in silico metabolic prediction. Moreover, in vivo efficacy of Ro 25-6981 after oral administration was evaluated in animal models of depression. When mixed with 5 different simulated gastrointestinal fluids, no loss of parent compound was observed after 6 h, indicating compound stability in the gastrointestinal environment. At the tested concentrations, Ro 25-6981 was shown to have transepithelial permeability with apparent permeability (P) values comparable to highly permeable drugs. Ro 25-6981 was metabolized within 30 min in human liver microsomes, and the metabolic prediction data showed glucuronidation and sulfation as potential metabolic pathways. The in vivo efficacy data suggested that Ro 25-6981, when administered orally at 30 mg/kg, exhibits antidepressant-like activity following oral administration with efficacy comparable to traditional antidepressants that is both dose- and time-dependent. Overall, due to optimal gastrointestinal stability, oral permeability, and oral efficacy, Ro 25-6981 can be a potential therapeutic option for the treatment of depression.
Ro 25-6981 是一种高效且选择性的 N-甲基-D-天冬氨酸受体阻断剂，已被证明具有快速和持续的抗抑郁活性。在本研究中，我们通过评估胃肠道稳定性、跨上皮通透性、在人肝微粒体中的稳定性和计算机代谢预测来报告 Ro 25-6981 的生物制药特征。此外，还在抑郁动物模型中评估了 Ro 25-6981 口服给药后的体内疗效。当与 5 种不同的模拟胃肠道液体混合时，在 6 小时后未观察到母体化合物的损失，表明化合物在胃肠道环境中的稳定性。在测试的浓度下，Ro 25-6981 表现出跨上皮通透性，表观渗透（P）值可与高渗透性药物相媲美。Ro 25-6981 在人肝微粒体中在 30 分钟内被代谢，代谢预测数据表明葡萄糖醛酸化和硫酸化可能是潜在的代谢途径。体内疗效数据表明，Ro 25-6981 以 30mg/kg 的剂量口服给药时，在口服给药后表现出抗抑郁样活性，其疗效与传统抗抑郁药相当，且具有剂量和时间依赖性。总体而言，由于 Ro 25-6981 具有最佳的胃肠道稳定性、口服渗透性和口服疗效，因此它可能成为治疗抑郁症的一种潜在治疗选择。
