Wang Wei, Tian Dan-Dan, Zheng Bin, Wang Di, Tan Qing-Rong, Wang Chuan-Yue, Zhang Zhang-Jin
School of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China (W.W., D.-D.T., Z.-J.Z.); College of Life Science, Jilin University, Changchun, Jilin, China (B.Z., D.W.); Department of Psychiatry, Fourth Military Medical University, Xi'an, Shaanxi, China (Q.-R.T.); and Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing, China (C.-Y.W.).
School of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China (W.W., D.-D.T., Z.-J.Z.); College of Life Science, Jilin University, Changchun, Jilin, China (B.Z., D.W.); Department of Psychiatry, Fourth Military Medical University, Xi'an, Shaanxi, China (Q.-R.T.); and Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing, China (C.-Y.W.)
Drug Metab Dispos. 2015 Jul;43(7):1147-53. doi: 10.1124/dmd.114.062653. Epub 2015 May 6.
Our previous studies have shown the therapeutic efficacy and underlying mechanisms of Peony-Glycyrrhiza Decoction (PGD), an herbal preparation, in treating antipsychotic-induced hyperprolactinemia in cultured cells, animal models, and human subjects. In the present study, we further evaluated pharmacokinetic interactions of PGD with clozapine (CLZ) in human liver microsomes (HLM), recombinantly expressed cytochrome P450s (P450s), and flavin-containing monooxygenases (FMOs). CLZ metabolites, N-demethyl-clozapine and clozapine-N-oxide, were measured. PGD, individual peony and glycyrrhiza preparations, and the two individual preparations in combination reduced production of CLZ metabolites to different extents in HLM. While the known bioactive constituents of PGD play a relatively minor role in the kinetic effects of PGD on P450 activity, PGD as a whole had a weak-to-moderate inhibitory potency toward P450s, in particular CYP1A2 and CYP3A4. FMOs are less actively involved in mediating CLZ metabolism and the PGD inhibition of CLZ. These results suggest that PGD has the capacity to suppress CLZ metabolism in the human liver microsomal system. This suppression is principally associated with the inhibition of related P450 activity but not FMOs. The present study provides in vitro evidence of herb-antipsychotic interactions.
我们之前的研究已表明，芍药甘草汤（PGD）这种草药制剂在培养细胞、动物模型和人体受试者中治疗抗精神病药物所致高催乳素血症的治疗效果及潜在机制。在本研究中，我们进一步评估了PGD与氯氮平（CLZ）在人肝微粒体（HLM）、重组表达的细胞色素P450（P450）和含黄素单加氧酶（FMO）中的药代动力学相互作用。测定了CLZ的代谢产物N-去甲基氯氮平和氯氮平氮氧化物。PGD、芍药和甘草的单一制剂以及二者的联合制剂在HLM中不同程度地降低了CLZ代谢产物的生成。虽然PGD已知的生物活性成分在PGD对P450活性的动力学效应中作用相对较小，但PGD整体对P450具有弱至中度的抑制效力，尤其是对CYP1A2和CYP3A4。FMO在介导CLZ代谢及PGD对CLZ的抑制作用中参与程度较低。这些结果表明，PGD有能力在人肝微粒体系统中抑制CLZ代谢。这种抑制主要与相关P450活性的抑制有关，而非FMO。本研究提供了草药与抗精神病药物相互作用的体外证据。
