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.