The effects of herbal medicines on pharmacokinetic, toxicological, and pharmacodynamic properties of antipsychotic drugs in in vitro and in vivo models : implication for herb-drug interactions

Abstract

Schizophrenia is a serious mental illness with a life time prevalence of approximately 1 % of the whole population. It is devastating to most people who are afflicted but also highly treatable. The newer class of antipsychotics, including clozapine (CLZ) and olanzapine (OLZ), are currently used far more commonly. However, patients' compliance to antipsychotic medication are constantly influenced due to inefficacy or intolerable side effects. While herbal products have been widely used as an adjunctive therapy in the treatment of a broad range of conditions, it also has risen the risk of adverse pharmacokinetic interactions. Therefore, clinical outcome-related herb-antipsychotic interactions need further investigation. This thesis consists of three studies:

(1) Peony-Glycyrrhiza Decoction (PGD), a classic herbal formula, has been demonstrated to be effective in alleviating antipsychotic-induced hyperprolactinemia. We therefore evaluated pharmacokinetic interactions of PGD with CLZ in human liver microsomes (HLM), recombinant cytochrome P450s (rCYPs), and flavin-containing monooxygenases (FMOs). Results showed herbal materials (PGD, its individual herbal preparations, and a mixture of two individual herbal preparations) exhibited various potencies in inhibiting CLZ metabolism, with a highest suppression effect observed for PGD. FMO3 was proved in current study to play a limited role in CLZ oxidation and confirmed to be hardly affected by herbal addition. Besides, PGD displayed a weak to moderate inhibitory potential on activity of CYPs involved in CLZ metabolism; but its major constituents had minor effects.

(2) The pharmacokinetic influence of other four commonly used herbal drugs (Fructus Schisandrae, FS; Fructus Gardeniae, FG; Radix Rehmanniae, RR; and Radix Bupleuri, RB) on antipsychotic metabolism were determined in in vitro systems and animal models. CYPs were inhibited to some extent by FS, while negligibly influenced by other herbal extracts, including RR, FG, and RB. All the herbs tested inhibited CLZ metabolism in acute treatment but no significant effect was found after long-term combined therapy. Acute treatment with RB, RR or FS was also found to reduce systemic exposure of OLZ without alteration on its metabolite, which can be explained by the decreased absorption process of OLZ by herbal additions. Although kinetic parameters of OLZ were unaltered after the chronic co-administration of herbal extracts, physicians should be alert for the long-term use of RB, which increased CnorOLZ/COLZ, suggesting attenuated efficacy of OLZ for relieving psychotropic symptoms.

(3) In addition, OLZ is always criticized by its metabolic side effects. In this project, a combined use of berberine (BBR) was found to successfully prevent OLZ induced weight gain, by decreasing energy intake and reducing adipose accumulation. OLZ-associated lipid dysregulation was normalized after BBR treatment. More importantly, peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated to be activated in the adipose tissue but not in hypothalamic area during OLZ therapy; and BBR decreased adipose tissue expansion at least partly via modulation of PPARγ2.

This study provides scientific evidence for the safety use of herbal medicines when patients are prescribed with antipsychotics. Berberine, a widely-used nature compound, is also proposed as a promising agent for the improvement of antipsychotic-related metabolic syndrome.