马钱子的时辰药理学特性与其在小鼠体内的昼夜节律代谢和转运有关。
Chronotoxicity of Semen Strychni is associated with circadian metabolism and transport in mice.
机构信息
Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China.
Institution of Laboratory Animal, Jinan University, Guangzhou, China.
出版信息
J Pharm Pharmacol. 2021 Mar 6;73(3):398-409. doi: 10.1093/jpp/rgaa007.
OBJECTIVES
We aimed to determine the circadian responses of mice to Semen Strychni and to investigate the role of pharmacokinetics in generating chronotoxicity.
METHODS
Total extract of Semen Strychni was administered by oral gavage to wild-type (WT) and Bmal1-/- (a circadian clock-deficient model) mice at different circadian time points for toxicity (including survival) and pharmacokinetic characterization. Nephrotoxicity and neurotoxicity were evaluated by measuring plasma creatinine and creatine kinase BB (CK-BB), respectively. Drug metabolism and transport assays were performed using liver/intestine microsomes and everted gut sacs, respectively.
KEY FINDINGS
Semen Strychni nephrotoxicity and neurotoxicity as well as animal survival displayed significant circadian rhythms (the highest level of toxicity was observed at ZT18 and the lowest level at ZT2 to ZT6). According to pharmacokinetic experiments, herb dosing at ZT18 generated higher plasma concentrations (and systemic exposure) of strychnine and brucine (two toxic constituents) compared with ZT6 dosing. This was accompanied by reduced formation of both dihydroxystrychnine and strychnine glucuronide (two strychnine metabolites) at ZT18. Bmal1 ablation sensitized mice to Semen Strychni-induced toxicity (with increased levels of plasma creatinine and CK-BB) and abolished the time dependency of toxicity. Metabolism of Semen Strychni (strychnine and brucine) in the liver and intestine microsomes of WT mice was more extensive at ZT6 than at ZT18. These time differences in hepatic and intestinal metabolism were lost in Bmal1-/- mice. Additionally, the intestinal efflux transport of Semen Strychni (strychnine and brucine) was more extensive at ZT6 than ZT18 in WT mice. However, the time-varying transport difference was abolished in Bmal1-/- mice.
CONCLUSIONS
Circadian responses of mice to Semen Strychni are associated with time-varying efflux transport and metabolism regulated by the circadian clock (Bmal1). Our findings may have implications for optimizing phytotherapy with Semen Strychni via timed delivery.
目的
本研究旨在确定马钱子对小鼠昼夜节律的影响，并探讨药代动力学在产生时间毒性中的作用。
方法
采用口服灌胃的方式，在不同的昼夜时间点向野生型（WT）和 Bmal1-/-（昼夜节律时钟缺陷模型）小鼠给予马钱子总提取物，以进行毒性（包括生存）和药代动力学特征的研究。通过检测血浆肌酸酐和肌酸激酶 BB（CK-BB）来评估肾毒性和神经毒性。分别使用肝/肠微粒体和外翻肠囊进行药物代谢和转运试验。
主要发现
马钱子的肾毒性、神经毒性以及动物存活率均呈现出显著的昼夜节律（毒性最高水平出现在 ZT18，最低水平出现在 ZT2 到 ZT6）。根据药代动力学实验，ZT18 给药时生成的士的宁和马钱子碱（两种有毒成分）的血浆浓度（和全身暴露量）高于 ZT6 给药时。这伴随着 ZT18 时二羟基士的宁和士的宁葡萄糖醛酸（两种士的宁代谢物）形成减少。Bmal1 缺失使小鼠对马钱子诱导的毒性更为敏感（血浆肌酸酐和 CK-BB 水平升高），并消除了毒性的时间依赖性。WT 小鼠肝和肠微粒体中马钱子的代谢（士的宁和马钱子碱）在 ZT6 时比 ZT18 时更为广泛。在 Bmal1-/-小鼠中，这种肝和肠代谢的时间差异消失了。此外，WT 小鼠的肠内马钱子（士的宁和马钱子碱）外排转运在 ZT6 时比 ZT18 时更为广泛。然而，在 Bmal1-/-小鼠中，这种随时间变化的转运差异消失了。
结论
小鼠对马钱子的昼夜节律反应与受昼夜节律时钟（Bmal1）调节的时间变化的外排转运和代谢有关。我们的发现可能对通过定时给药优化马钱子植物疗法具有重要意义。
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