title: Peony-Glycyrrhiza Decoction, an Herbal Preparation, Inhibits Clozapine Metabolism via Cytochrome P450s, but Not Flavin-Containing Monooxygenase in In Vitro Models.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Tian
authors.affiliation: 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.).
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: 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.).
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Tan
authors.affiliation: 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.).
authors.forename: Chuan-Yue
authors.initials: CY
authors.lastname: Wang
authors.affiliation: 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.) zhangzj@hku.hk.
authors.forename: Zhang-Jin
authors.initials: ZJ
authors.lastname: Zhang
mesh_terms: D014150:Antipsychotic Agents / Q000378:metabolism*; D003024:Clozapine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038181:FMN Reductase / Q000378:metabolism*; D005260:Female; D006035:Glycyrrhiza / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D029596:Paeonia / Q000737:chemistry*; D010599:Pharmacokinetics; D028321:Plant Preparations / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D028321:Plant Preparations; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D038181:FMN Reductase; D003024:Clozapine