In Vitro Effects of Concomitant Use of Herbal Preparations on Cytochrome P450s Involved in Clozapine Metabolism

Herbal supplements are increasingly used in psychiatric practice. Our epidemiological study has identified several herbal preparations associated with adverse outcomes of antipsychotic therapy. In this study, we evaluated the in vitro effects of four herbal preparations—Radix Rehmanniae (RR), Fructus Schisandrae (FS), Radix Bupleuri (RB) and Fructus Gardeniae (FG)—on cytochrome P450s (CYPs) involved in the metabolism of clozapine in human liver microsomes (HLMs) and recombinant human cytochrome P450 enzymes (rCYPs). N-desmethylclozapine and clozapine N-oxide, two major metabolites of clozapine, were measured using high-performance liquid chromatography (HPLC). FG, RR and RB showed negligible inhibitory effects in both in vitro systems, with estimated half-maximal inhibitory concentrations (IC(50)) and apparent inhibitory constant values (K(i)) greater than 1 mg/mL (raw material), suggesting that minimal metabolic interaction occurs when these preparations are used concomitantly with clozapine. The FS extract affected CYP activity with varying potency; its effect on CYP 3A4-catalyzed clozapine oxidation was relatively strong (K(i): 0.11 mg/mL). Overall, the weak-to-moderate inhibitory effect of FS on in vitro clozapine metabolism indicated its potential role in herb-drug interaction in practice.