title: The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis.
abstract: Clozapine, an atypical antipsychotic agent, is highly effective in treatment-resistant schizophrenia; however, its major side effect is constipation. Instead of laxatives, rhein is a pharmacologically active component found in Rheum palmatum L., a medicinal herbal remedy for constipation. The purpose of this study is to determine whether rhein impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of clozapine in brain when used to relieve clozapine-induced constipation. Here, we have investigated not only the PK of clozapine in blood but also the effects of rhein on the PK of clozapine in blood and in brain extracellular fluid together with the PD effects on neurotransmitters in extracellular fluid. The concentrations of clozapine and norclozapine in biologic samples were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat medial prefrontal cortex (mPFC) produced by clozapine were assayed by high-performance liquid chromatography-electrochemical detection. The results demonstrate that the clozapine PK was nonlinear. Pretreatment with rhein for 7 days increased the total blood concentration of clozapine, but significantly reduced the unbound clozapine concentrations in the mPFC by approximately 3-fold. Furthermore, 7 days of rhein pretreatment thoroughly abolished the efflux of dopamine and its metabolite (3,4-dihydroxyphenylacetic acid) and altered the profile of homovanillic acid, another metabolite of dopamine, in the mPFC. In conclusion, rhein was found to substantially decrease clozapine and norclozapine concentrations in the mPFC dialysate, and this is accompanied by lower concentrations in the neurotransmitters in the same biophase. These findings suggest that a detailed clinical study for drug-drug interactions is recommended.
authors.affiliation: Institute of Traditional Medicine (M.-L.H., T.-H.T.) and Institute of Microbiology and Immunology (C.-H.L.), National Yang-Ming University, Taipei, Taiwan; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan (L.-C.L.); Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan (T.-H.T.); School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (T.-H.T.); and Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (T.-H.T.).
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Hou
authors.affiliation: Institute of Traditional Medicine (M.-L.H., T.-H.T.) and Institute of Microbiology and Immunology (C.-H.L.), National Yang-Ming University, Taipei, Taiwan; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan (L.-C.L.); Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan (T.-H.T.); School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (T.-H.T.); and Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (T.-H.T.).
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Institute of Traditional Medicine (M.-L.H., T.-H.T.) and Institute of Microbiology and Immunology (C.-H.L.), National Yang-Ming University, Taipei, Taiwan; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan (L.-C.L.); Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan (T.-H.T.); School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (T.-H.T.); and Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (T.-H.T.).
authors.forename: Lie-Chwen
authors.initials: LC
authors.lastname: Lin
authors.affiliation: Institute of Traditional Medicine (M.-L.H., T.-H.T.) and Institute of Microbiology and Immunology (C.-H.L.), National Yang-Ming University, Taipei, Taiwan; National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan (L.-C.L.); Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan (T.-H.T.); School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (T.-H.T.); and Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (T.-H.T.) thtsai@ym.edu.tw.
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D001921:Brain / Q000166:cytology*; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009068:Movement / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000880:Anthraquinones; D018377:Neurotransmitter Agents; C058272:norclozapine; D003024:Clozapine; C020491:rhein