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 and pharmacodynamics of clozapine in brain when used to relieve clozapine-induced constipation. Here we have investigated not only pharmacokinetics of clozapine in blood but also the effects of rhein on the pharmacokinetics of clozapine in blood and in brain extracellular fluid (ECF) together with the pharmacodynamics effects on neurotransmitters in ECF. The concentration of clozapine and norclozapine in biological samples were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat mPFC produced by clozapine were assayed by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The results demonstrate that clozapine pharmacokinetics was nonlinear. Pretreatment with rhein for 7 days increased 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 (DOPAC) and altered the profile of HVA, 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.
- drug distribution
- drug-drug interactions
- The American Society for Pharmacology and Experimental Therapeutics