背景:乌头的组合(川武,CW)和半夏(Thunb。)Breit(半夏,BX)在18种不相容药物(EIM)中形成一对草药对,表示BX和CW不兼容。然而,对这种不相容机制的科学理解,特别是相应的药物-药物相互作用(DDI),仍然复杂和不清楚。
目的:本研究旨在基于药代动力学和鸡尾酒方法解释CW和BX之间的DDI和潜在的不相容性机制。
方法:建立超高效液相色谱-串联质谱法用于药代动力学和鸡尾酒研究。为了探索BX和CW之间的DDI,在药代动力学研究中,在施用CW和BX-CW草药对提取物后,在大鼠血浆中测定10种化合物。在鸡尾酒试验中,利用5种探针底物的药代动力学参数来评估BX对细胞色素P450(CYP)同工酶的影响(氨苯砜用于CYP3A4,非那西丁用于CYP1A2,右美沙芬用于CYP2D6,甲苯磺丁胺用于CYP2C9,奥美拉唑用于CYP2C19).最后,整合了CW和BX的DDI和不相容机制,以解释EIM理论的合理性。
结果:BX不仅增强乌头碱和苯甲酰乌头碱的吸收,而且加速了中乌头碱的代谢,苯甲酰基美松碱,松戈林,还有Fuziline.此外,BX影响CYP酶的活性,调节有毒化合物的代谢。
结论:BX改变了CYP酶的活性,因此影响CW有毒化合物的代谢。这种不相容性机制可能与这些有毒化合物在体内的吸收增加有关。
BACKGROUND: The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear.
OBJECTIVE: This study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach.
METHODS: Ultraperformance liquid chromatography-tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX-CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory.
RESULTS: BX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds.
CONCLUSIONS: BX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.