School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region.
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region.
Life Sci. 2022 Sep 15;305:120743. doi: 10.1016/j.lfs.2022.120743. Epub 2022 Jul 1.
Carboxylesterase (CES) plays an essential role in the hydrolysis of ester prodrugs. Our study explored the inhibitions of Radix Scutellariae flavones, including baicalein (B), baicalin (BG), wogonin (W), wogonoside (WG), oroxylin A (OXA) and oroxylin A-7-O-glucuronide (OAG), on CES-mediated hydrolysis of seven prodrugs (capecitabine, clopidogrel, mycophenolate mofetil, dabigatran etexilate, acetylsalicylic acid, prasugrel and irinotecan).
In vitro screenings were developed by incubating the flavones with prodrugs in rat plasma, intestine S9 and liver S9. Docking simulations were conducted using AMDock v1.5.2. In vivo evaluations were performed in rats co-administered with the selected flavone and prodrug via oral gavage/intravenous administration for five consecutive days.
The in vitro investigation showed that B and OXA demonstrated strongest inhibitions on the hydrolysis of irinotecan followed by dabigatran in rat plasma, intestine S9 and liver S9. Consistent results showed in the molecular docking analyses. Additionally, in rats receiving irinotecan, B/OXA intravenous and oral pre-treatments both led to reduction trends on the active metabolite SN-38 formation in plasma. Besides, significant decreases of SN-38/irinotecan plasma concentration ratios were found in the B/OXA oral pre-treatment group with quicker and stronger inhibition potential in OXA pre-treatment than that from B pre-treatment. OXA oral pre-treatment was also found to be able to significantly inhibit intestinal CES2 activities at 0.5 h and 5 h after irinotecan administration.
Our current findings for the first time alert on potential CES-mediated HDIs between RS flavones and prodrugs, which provide a constructive information referring to rational drug combinations in clinical practice.
羧酸酯酶（CES）在酯前药的水解中起着至关重要的作用。本研究探讨了黄芩黄酮，包括黄芩素（B）、黄芩苷（BG）、汉黄芩素（W）、汉黄芩苷（WG）、野黄芩素（OXA）和野黄芩素-7-O-葡萄糖醛酸苷（OAG），对 CES 介导的七种前药（卡培他滨、氯吡格雷、霉酚酸酯、达比加群酯、阿司匹林、普拉格雷和伊立替康）水解的抑制作用。
通过在大鼠血浆、肠 S9 和肝 S9 中孵育黄酮和前药，进行体外筛选。采用 AMDock v1.5.2 进行对接模拟。在大鼠中进行体内评价，连续五天通过口服灌胃/静脉注射给予选定的黄酮和前药。
体外研究表明，B 和 OXA 对大鼠血浆、肠 S9 和肝 S9 中伊立替康的水解表现出最强的抑制作用，其次是达比加群。分子对接分析也得到了一致的结果。此外，在接受伊立替康的大鼠中，B/OXA 静脉和口服预处理均导致血浆中活性代谢物 SN-38 形成的减少趋势。此外，在 B/OXA 口服预处理组中，SN-38/伊立替康血浆浓度比值显著降低，且 OXA 预处理的抑制作用快于 B 预处理。OXA 口服预处理还能显著抑制伊立替康给药后 0.5 h 和 5 h 时的肠道 CES2 活性。
本研究首次发现 RS 黄酮与前药之间存在潜在的 CES 介导的 HID，为临床实践中合理的药物联合提供了有建设性的信息。
