title: Pharmacokinetic Evaluation of Clozapine in Concomitant Use of Radix Rehmanniae, Fructus Schisandrae, Radix Bupleuri, or Fructus Gardeniae in Rats.
abstract: 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.
authors.affiliation: School of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China. tiandd86@hotmail.com.
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. wwei0825@gmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, the fourth Military Medical University, Xi'an 710032, Shaanxi, China. xskzhu@fmmu.edu.cn.
authors.forename: Hua-Ning
authors.initials: HN
authors.lastname: Wang
authors.affiliation: School of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China. stephens@hku.hk.
authors.forename: Stephen Cho Wing
authors.initials: SC
authors.lastname: Sze
authors.affiliation: School of Chinese Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China. zhangzj@hku.hk.
authors.forename: Zhang-Jin
authors.initials: ZJ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage*; D041743:Herb-Drug Interactions; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008297:Male; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy; D014018:Tissue Distribution
chemical_list: D004365:Drugs, Chinese Herbal; D003024:Clozapine
keywords: clozapine; herb-drug interaction; herbal medicine; metabolism; pharmacokinetics