Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China.
Zhuhai United Laboratories, Zhuhai, Guangdong, China.
J Pharm Pharmacol. 2021 Mar 8;73(4):535-544. doi: 10.1093/jpp/rgaa060.
Identifying drugs with time-varying efficacy or toxicity, and understanding the underlying mechanisms would help to improve treatment efficacy and reduce adverse effects. In this study, we uncovered that the therapeutic effect of Fuzi (the lateral root of Aconitum carmichaelii Debeaux) depended on the dosing time in mice with adenine-induced chronic kidney disease (CKD).
The Fuzi efficacy was determined by biomarker measurements [i.e. plasma creatinine (CRE), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG)], as well as inflammation, fibrosis and histological analyses. Circadian regulation of Fuzi pharmacokinetics and efficacy was evaluated using brain and muscle Arnt-like protein-1 (Bmal1)-deficient (Bmal1-/-) mice.
The Fuzi efficacy was higher when the drug was dosed at ZT10 and was lower when the drug was dosed at other times (ZT2, ZT6, ZT14, ZT18 and ZT22) according to measurements of plasma CRE, BUN and urinary NAG. Consistently, ZT10 (5 PM) dosing showed a stronger protective effect on the kidney (i.e. less extensive tubular injury) as compared to ZT22 (5 AM) dosing. This was supported by lower levels of inflammatory and fibrotic factors (IL-1β, IL-6, Tnf-α, Ccl2, Tgfb1 and Col1a1) at ZT10 than at ZT22. Pharmacokinetic analyses showed that the area under the curve (AUC) values (reflective of systemic exposure) and renal distribution of aconitine, hypaconitine and mesaconitine (three putative active constituents) for Fuzi dosing at ZT10 were significantly higher than those for herb dosing at ZT22, suggesting a role of circadian pharmacokinetics in Fuzi chronoefficacy. Drug efficacy studies confirmed that aconitine, hypaconitine and mesaconitine possessed a kidney-protecting effect. In addition, genetic knockout of Bmal1 in mice abolished the time-dependency of Fuzi pharmacokinetics and efficacy. This reinforced the existence of chronoefficacy for Fuzi and supported the role of circadian pharmacokinetics in Fuzi chronoefficacy.
The efficacy of Fuzi against CKD depends on the dosing time in mice, which is associated with circadian pharmacokinetics of the three main active constituents (i.e. aconitine, hypaconitine and mesaconitine). These findings highlight the relevance of dosing time in the therapeutic outcomes of herbal medicines.
鉴定具有时变疗效或毒性的药物，并了解其潜在机制，有助于提高治疗效果，减少不良反应。本研究揭示了乌头（川乌的侧根）在腺嘌呤诱导的慢性肾脏病（CKD）小鼠中的治疗效果取决于给药时间。
通过生物标志物测量[即血浆肌酐（CRE）、血尿素氮（BUN）和尿 N-乙酰-β-D-氨基葡萄糖苷酶（NAG）]以及炎症、纤维化和组织学分析来确定乌头的疗效。使用脑和肌肉芳香烃受体核转录因子样蛋白-1（Bmal1）缺陷（Bmal1-/-）小鼠评估乌头药代动力学和疗效的昼夜节律调节。
根据血浆 CRE、BUN 和尿 NAG 的测量结果，当药物在 ZT10 时给药时，乌头的疗效更高，而当药物在其他时间（ZT2、ZT6、ZT14、ZT18 和 ZT22）时给药时，乌头的疗效更低。同样，与 ZT22（5 AM）给药相比，ZT10（5 PM）给药对肾脏（即肾小管损伤程度较轻）具有更强的保护作用。这一结果得到了炎症和纤维化因子（IL-1β、IL-6、Tnf-α、Ccl2、Tgfb1 和 Col1a1）水平的支持，ZT10 时的水平低于 ZT22 时的水平。药代动力学分析表明，当药物在 ZT10 时给药时，乌头中乌头碱、次乌头碱和新乌头碱（三种潜在的活性成分）的 AUC 值（反映系统暴露）和肾分布明显高于药物在 ZT22 时给药，提示昼夜药代动力学在乌头的chronoefficacy 中起作用。药物疗效研究证实，乌头碱、次乌头碱和新乌头碱具有肾脏保护作用。此外，小鼠中 Bmal1 的基因敲除消除了乌头药代动力学和疗效的时间依赖性。这进一步证实了乌头的chronoefficacy 的存在，并支持昼夜药代动力学在乌头 chronoefficacy 中的作用。
乌头对 CKD 的疗效取决于小鼠的给药时间，这与三种主要活性成分（即乌头碱、次乌头碱和新乌头碱）的昼夜药代动力学有关。这些发现强调了给药时间在草药治疗效果中的重要性。
