Clozapine affects the pharmacokinetics of risperidone and inhibits its metabolism and P-glycoprotein–mediated transport in vivo and in vitro: A safety attention to antipsychotic polypharmacy with clozapine and risperidone

Antipsychotic polypharmacy (APP), as one maintenance treatment strategy in patients with schizophrenia, has gained popularity in real-world clinical settings. Risperidone (RIS) and clozapine (CLZ) are the most commonly prescribed second-generation antipsychotics, and they are often used in combination as APP. In this study, the pharmacokinetics of RIS and CLZ in rats were examined after co-administration to explore the reliability and rationality of co-medication with RIS and CLZ. In addition, the effects of CLZ on RIS metabolism and transport in vitro were investigated. The results illustrated that in the 7-day continuous administration test in rats, when co-administered with CLZ, the area under curve and peak concentrations of RIS were increased by 2.2- and 3.1-fold at the first dose, respectively, increased by 3.4- and 6.2-fold at the last dose, respectively. The metabolite-to-parent ratio of RIS was approximately 22% and 33% lower than those of RIS alone group at the first and last doses, respectively. Moreover, CLZ significantly increased RIS concentrations in the brain (3.0–4.8 folds) and cerebrospinal fluid (2.1–3.5 folds) in rats, which was slightly lower than the impact of verapamil on RIS after co-medication. Experiments in vitro indicated that CLZ competitively inhibited the conversion of RIS to 9-hydroxy-RIS with the inhibition constants of 1.36 and 3.0 μM in rat and human liver microsomes, respectively. Furthermore, the efflux ratio of RIS in Caco-2 monolayers was significantly reduced by CLZ at 1 μM. Hence, CLZ may affect the exposure of RIS by inhibiting its metabolism and P-glycoprotein-mediated transport. These findings highlighted that APP with RIS and CLZ might increase the plasma concentrations of RIS and 9-hydroxy-RIS beyond the safety ranges and cause toxic side effects. [Display omitted] •RIS exposure in rat plasma and brain was obviously increased when combined with CLZ.•CLZ competitively inhibited RIS metabolism in RLMs and HLMs.•CLZ significantly decreased the efflux ratio of RIS by Caco-2 cell monolayers.•APP with RIS and CLZ may increase the exposure of RIS and cause toxic side effects.