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.
Highlights
Clozapine (CLZ), a tricyclic dibenzodiazepine antipsychotic drug, is commonly prescribed for the long-term maintenance treatment of schizophrenia
The method sensitivity in plasma was determined by the LLOQ, which were 9.8, 13.6, and 17.1 nM for CLZ, norCLZ, and CLZ clozapine N-oxide (N-oxide), respectively
Previous studies have demonstrated that schizophrenia patients have a higher prevalence of cardiovascular disease, diabetes mellitus, and metabolic syndrome than the general population, while antipsychotic drugs can aggravate glucose and lipid metabolism disorders [17,18]
Summary
Clozapine (CLZ), a tricyclic dibenzodiazepine antipsychotic drug, is commonly prescribed for the long-term maintenance treatment of schizophrenia. CLZ is therapeutically effective for treating patients with schizophrenia that is refractory to other neuroleptics, without producing significant extrapyramidal symptoms. The associated adverse effects, such as hypersalivation, idiosyncratic hepatotoxicity, agranulocytosis, and cardiactoxicity, restrict its clinical use [1,2]. Herbal medicines are increasingly used in the treatment of schizophrenia to improve the therapeutic efficacy and reduce adverse side effects. Our previous epidemiological survey showed that approximately 37%. Of schizophrenia patients received antipsychotics in combination with herbal medicines, including. Radix Rehmanniae (RR, Di-Huang), derived from the roots of Rehmannia glutinosa (Gaertn.) DC., is a traditional Chinese
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