Gao You, Yang Chunmiao, Wang Lingchao, Xiang Yanan, Zhang Wenpeng, Li Yunfeng, Zhuang Xiaomei
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Front Pharmacol. 2020 Nov 27;11:588127. doi: 10.3389/fphar.2020.588127. eCollection 2020.
YL-IPA08, exerting rapid antidepressant-like and anxiolytic-like effects on behaviors by translocator protein (TSPO) mediation, is a novel compound that has been discovered and developed at our institute. Fit-for-purpose pharmacokinetic properties is urgently needed to be discovered as early as possible for a new compound. YL-IPA08 exhibited low bioavailability (∼6%) during the preliminary pharmacokinetics study in rats after oral administration. Our aim was to determine how metabolic disposition by microsomal P450 enzymes in liver and intestine limited YL-IPA08's bioavailability and further affected brain penetration to the target. Studies of metabolic stability and permeability combined with oral bioavailability, panel CYP inhibitor co-administration via different routes, and double cannulation rats were conducted to elucidate the intestinal and hepatic first-pass effect of YL-IPA08 on bioavailability. Unbound brain-to-plasma ratio ( ) in rats was determined at steady state. Results indicated that P450-mediated elimination appeared to be important for its extensive first-pass effect with comparative contribution of gut (35%) and liver (17%), and no significant species difference was observed. The unbound concentration of YL-IPA08 in rat brain (6.5 pg/ml) was estimated based on (0.18) and was slightly higher than TSPO-binding activity (4.9 pg/ml). Based on the onset efficacy of YL-IPA08 toward TPSO in brain and , therapeutic human plasma concentration was predicted to be ∼27.2 ng/ml would easily be reached even with unfavorable bioavailability.
YL-IPA08是一种在我们研究所发现并研发的新型化合物，它通过转运蛋白（TSPO）介导，对行为具有快速的抗抑郁样和抗焦虑样作用。对于一种新化合物而言，迫切需要尽早发现适合其用途的药代动力学特性。在大鼠口服给药后的初步药代动力学研究中，YL-IPA08表现出较低的生物利用度（约6%）。我们的目的是确定肝脏和肠道中的微粒体P450酶的代谢处置如何限制YL-IPA08的生物利用度，并进一步影响其向靶点的脑内渗透。通过进行代谢稳定性和渗透性研究，并结合口服生物利用度、经不同途径联合给予CYP抑制剂以及双插管大鼠实验，以阐明YL-IPA08在肠道和肝脏的首过效应及其对生物利用度的影响。在稳态下测定大鼠的非结合脑血比（ ）。结果表明，P450介导的消除似乎对其广泛的首过效应很重要，肠道（35%）和肝脏（17%）具有相对贡献，且未观察到明显的种属差异。根据 （0.18）估算大鼠脑中YL-IPA08的非结合浓度（6.5 pg/ml），略高于TSPO结合活性（4.9 pg/ml）。基于YL-IPA08对脑中TPSO的起效疗效以及 ，预计即使生物利用度不佳，治疗性人体血浆浓度也很容易达到约27.2 ng/ml。
