Systemic administration of D2 antagonist raclopride inhibits CYP1A2 in the rat model of isolated perfused liver

Raclopride (CAS 98185-20-7) is a synthetic benzamide related to sulpiride eliciting selective antagonism on dopamine D2 receptors (Ericson et al 1996). It was investigated for the treatment of psychoses (Seeman 2002) and serves frequently in experimental pharmacology as a representative of selective D2 receptor blocking drugs (Seeman 2002; Eltayb et al 2005; Ginovart et al 2009). Up to date, in the literature available there is no data on possible influence of raclopride on the metabolic activity of cytochrome P450 enzymes. Recently it was published, that brain mesolimbic and tuberoinfundibular dopaminergic pathways influence the activity of hepatal cytochrome oxidase system (Wojcikowski et al 2007; Wojcikowski et al 2008). One of possible explanation considered could be changes in hormone and cytokine levels influencing some of receptor (e.g. glucocorticoid receptor, pregnane X receptor or constitutive androstane receptor) regulating P450 proteins (Wojcikowski et al 2007; 2008). Our study addressed whether systemic administration of raclopride (D2 receptor antagonist) may influence the metabolic activity of rat CYP1A2, CYP2C6/11 or CYP2D2 in the model of isolated perfused liver. It was taken into consideration that CYP2C6/11 is a rat orthologue of human CYP2C9 (Matuskova et al 2009), CYP2D1 is rat orthologue of human CYP2D6 (Soucek & Gut 1992). The most used marker of CYP2D6 dextromethorphan is metabolized by CYP2D2 in rats (Kobayashi et al 2002). The model of isolated perfused rat liver was selected because it reflects most of physiological and biochemical linkages in the liver-mediated metabolism of xenobiotics.