Pharmacokinetic changes of clozapine and norclozapine in a rat model of non-alcoholic fatty liver disease induced by orotic acid.

Impaired in vitro oxidation of clozapine has been reported in steatotic rat liver due to downregulation of cytochrome P450 (CYP) 1A. Pharmacokinetic changes of clozapine and its major metabolite, norclozapine, were evaluated in a rat model of non-alcoholic fatty liver disease (NAFLD) induced by orotic acid. Significantly slower in vitro CLint for formation of norclozapine from clozapine was observed in NAFLD rats than in control rats as a result of the reduced protein expression and metabolic activity of CYP1A1/2. However, systemic exposures to clozapine in NAFLD rats were comparable to those in controls after intravenous (4 mg/kg) and oral (10 mg/kg) administration of clozapine. Of note, the AUC of the norclozapine and AUCnorclozapine/AUCclozapine ratio following intravenous and oral administration of clozapine rather increased significantly in NAFLD rats, as a result of the slowed subsequent metabolism of norclozapine via CYP1A1/2. Steady-state brain concentrations of both clozapine and norclozapine were significantly higher in NAFLD rats than those in control rats following intravenous infusion of clozapine. Increased systemic exposure to norclozapine and elevated brain concentrations of clozapine and norclozapine observed in NAFLD rats imply that further studies are warranted on the pharmacotherapy of clozapine in patients with pre-existing or drug-induced hepatic steatosis.