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

Abstract

1. 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.

2. Significantly slower in vitro CL_int 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.

3. Of note, the AUC of the norclozapine and AUC_norclozapine/AUC_clozapine 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.

4. 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.

Keywords:

• Clozapine
• norclozapine
• pharmacokinetics
• non-alcoholic fatty liver disease
• CYP1A
• rat

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government [No. 2015R1C1A1A01051599 (MSIP), 2018R1A6A1A03025108 (Ministry of Education), and 2019R1F1A1052243 (MSIT)] and by the Research Fund, 2019 of The Catholic University of Korea.