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.
Toxicol Appl Pharmacol
; 422: 115560, 2021 07 01.
Article
en En
| MEDLINE
| ID: mdl-33957192
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Antipsicóticos
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Microsomas Hepáticos
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Clozapina
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
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Risperidona
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Absorción Intestinal
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Mucosa Intestinal
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2021
Tipo del documento:
Article