Tian Dan-Dan, Wang Wei, Wang Hua-Ning, Sze Stephen Cho Wing, Zhang Zhang-Jin
School of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China.
Department of Psychiatry, the fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Molecules. 2016 May 27;21(6):696. doi: 10.3390/molecules21060696.
Radix Rehmanniae, Fructus Schisandrae, Radix Bupleuri, and Fructus Gardeniae are often used alongside with clozapine (CLZ) for schizophrenia patients in order to reduce side effects and enhance therapeutic efficacy. However, worse outcomes were observed raising concern about a critical issue, herb-drug interactions, which were rarely reported when antipsychotics were included. This study aims to determine whether the concomitant use of these herbal medicines affects the pharmacokinetic characteristics of CLZ in rat models. Rats were given a single or multiple intraperitoneal injections of 10 mg/kg CLZ, either alone or with individual herbal water extracts administered orally. CLZ and its two inactive metabolites, norclozapine and clozapine N-oxide, were determined by high-performance liquid chromatography/tandem mass spectrometry. In the acute treatment, the formation of both metabolites was reduced, while no significant change was observed in the CLZ pharmacokinetics for any of the herbal extracts. In the chronic treatment, none of the four herbal extracts significantly influenced the pharmacokinetic parameters of CLZ and its metabolites. Renal and liver functions stayed normal after the 11-day combined use of herbal medicines. Overall, the four herbs had limited interaction effect on CLZ pharmacokinetics in the acute and chronic treatment. Herb-drug interaction includes both pharmacokinetic and pharmacodynamic mechanisms. This result gives us a hint that pharmacodynamic herb-drug interaction, instead of pharmacokinetic types, may exist and need further confirmation.
地黄、五味子、柴胡和栀子常与氯氮平（CLZ）联合用于精神分裂症患者，以减少副作用并提高治疗效果。然而，观察到的较差结果引发了人们对一个关键问题的关注，即草药-药物相互作用，而当使用抗精神病药物时，这一问题很少被报道。本研究旨在确定这些草药的联合使用是否会影响大鼠模型中氯氮平的药代动力学特征。大鼠单独或与口服给予的单一草药水提取物一起，腹腔注射10mg/kg氯氮平一次或多次。通过高效液相色谱/串联质谱法测定氯氮平及其两种无活性代谢物去甲氯氮平和氯氮平N-氧化物。在急性治疗中，两种代谢物的形成均减少，而对于任何一种草药提取物，氯氮平的药代动力学均未观察到显著变化。在慢性治疗中，四种草药提取物均未显著影响氯氮平及其代谢物的药代动力学参数。在联合使用草药11天后，肾功能和肝功能保持正常。总体而言，这四种草药在急性和慢性治疗中对氯氮平药代动力学的相互作用作用有限。草药-药物相互作用包括药代动力学和药效学机制。这一结果提示我们，可能存在药效学方面的草药-药物相互作用而非药代动力学类型的相互作用，需要进一步证实。
