%0 Journal Article
%T Comparative Cytochrome P450 In Vitro Inhibition by Atypical Antipsychotic Drugs
%A Guillermo Gervasini
%A Maria J. Caballero
%A Juan A. Carrillo
%A Julio Benitez
%J ISRN Pharmacology
%D 2013
%R 10.1155/2013/792456
%X The goal of this study was to assess in human liver microsomes the inhibitory capacity of commonly used antipsychotics on the most prominent CYP450 drug metabolizing enzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A). Chlorpromazine was the only antipsychotic that inhibited CYP1A2 activity ( £¿¦ÌM), whilst levomepromazine, chlorpromazine, and thioridazine significantly decreased CYP2D6-mediated formation of -hydroxybufuralol (IC50 range, 3.5¨C25.5£¿¦ÌM). Olanzapine inhibited CYP3A-catalyzed production of , and -hydroxymidazolam ( and 42.20£¿¦ÌM, resp.). In contrast, risperidone ( £¿¦ÌM) and levomepromazine ( £¿¦ÌM) showed selectivity towards the inhibition of midazolam -hydroxylation reaction, and haloperidol did so towards -hydroxylation (IC50 of 2.76£¿¦ÌM). Thioridazine displayed a of 1.75£¿¦ÌM and an inhibitory potency of 1.57 on CYP2D6, suggesting a potential to induce in vivo interactions. However, with this exception, and given the observed values, the potential of the assayed antipsychotics to produce clinically significant inhibitions of CYP450 isoforms in vivo seems limited. 1. Introduction In contrast to conventional neuroleptics, atypical antipsychotics have been shown to be effective against both positive and negative symptoms of schizophrenia while showing a reduced propensity to induce extrapyramidal effects [1]. The cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6, and CYP3A enzymes are responsible for the metabolism of many of these and other psychoactive compounds [2¨C8]. Traditionally, studies on pharmacological interactions involving antipsychotics have examined the inhibition of these isoforms by drugs that are concomitantly administered, especially serotonin reuptake inhibitors [9¨C13]. However, there is still limited information on the capacity of antipsychotics to inhibit the metabolism of other coadministered drugs and the potentially clinically significant interactions that could arise [14]. In this paper we have assessed the potential for nine of the most commonly used atypical antipsychotics (clozapine, olanzapine, iloperidone, quetiapine, haloperidol, chlorpromazine, levomepromazine, thioridazine, and risperidone) and abaperidone (7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymethyl)chromen-4-one; FI-8602), an underdevelopment compound with a potentially atypical antipsychotic profile [15, 16], to cause significant drug-drug interactions by using in vitro inhibition techniques in human liver microsomes. 2. Methods 2.1. Reference Substances Abaperidone and iloperidone were gifts from Centro de Investigaci¨®n Farmac¨¦utica, Grupo
%U http://www.hindawi.com/journals/isrn.pharmacology/2013/792456/