Herb-drug interaction between Dahuang-Gancao decoction and clozapine: A pharmacokinetic study in rats

IF 4.2 Q2 CHEMISTRY, MULTIDISCIPLINARY

Results in Chemistry Pub Date : 2025-09-14 DOI:10.1016/j.rechem.2025.102665

Kejun Liu , Zhizhong Xu , Jianfeng Zhang , Kaining Zhang , Chunyan Wen , Jindong Chen , Qingjiang Lin , Xianhua Zhang

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Abstract

Dahuang-Gancao decoction (DGD) comprises Rhei Radix et Rhizoma and Glycyrrhizae Radix et Rhizoma at ratio of 4:1, which is usually applied for relieving clozapine-induced constipation in clinical practice. However, the herb-drug interactions involving antipsychotics with narrow therapeutic range have rarely been reported. We investigated a potential pharmacokinetic-based interaction between DGD and clozapine based on in vitro and in vivo studies. Rats received a single injection of clozapine (5 mg/kg, i.v.,) 30 min after pretreatment with DGD (p.o.) for 3 days or 14 days. The concentrations of clozapine and its metabolites in rat plasma were measured by high-performance liquid chromatography-tandem mass spectrometry. The effects of DGD on protein expression of cytochrome P450 (CYP450) in vivo and the binding of plasma proteins to clozapine in vitro were determined. After 3-day pretreatment with DGD, there were no significant changes in the pharmacokinetics of clozapine or its metabolites. A significant increase in certain pharmacokinetic parameters of clozapine was observed after 14-day pretreatment with DGD. Protein expression of CYP1A2 was inhibited via multiple dosage of DGD in time-dependent manner. The plasma protein binding rate in various concentrations of clozapine was reduced significantly in vitro after DGD therapy. The effects upon pharmacokinetics of clozapine after DGD pretreatment could be attributed to inhibition of CYP1A2 expression and a decrease in plasma protein binding. Hence, caution must be applied to some drugs with a narrow therapeutic index to avoid the potential risk of herb-drug interactions in clinical practice.

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大黄甘草汤与氯氮平的相互作用：大鼠药动学研究

大黄肝草汤（DGD）由大黄与甘草组成，比例为4:1，临床上常用于缓解氯氮平引起的便秘。然而，涉及抗精神病药物治疗范围狭窄的中草药相互作用却鲜有报道。基于体内和体外研究，我们研究了DGD和氯氮平之间潜在的药代动力学相互作用。大鼠在DGD （p.o）预处理后30分钟单次注射氯氮平（5 mg/kg，静脉注射），连续3天或14天。采用高效液相色谱-串联质谱法测定大鼠血浆中氯氮平及其代谢物的浓度。测定DGD对体内细胞色素P450 （CYP450）蛋白表达及体外血浆蛋白与氯氮平结合的影响。DGD预处理3天后，氯氮平及其代谢物的药代动力学无明显变化。经DGD预处理14天后，氯氮平的某些药代动力学参数显著增加。多剂量DGD对CYP1A2蛋白表达的抑制呈时间依赖性。DGD治疗后，血浆蛋白结合率在不同浓度氯氮平下均显著降低。DGD预处理对氯氮平药代动力学的影响可能与抑制CYP1A2表达和降低血浆蛋白结合有关。因此，对于一些治疗指数较窄的药物，在临床实践中必须谨慎使用，以避免潜在的中草药相互作用风险。

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