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.

摘要

1. 受损体外氯氮平氧化已经报道了脂肪肝的大鼠肝由于与细胞色素P450（CYP）1A的下调。在由乳清酸诱导的非酒精性脂肪肝疾病（NAFLD）大鼠模型中评估了氯氮平及其主要代谢物去氯氮平的药代动力学变化。

2. 由于CYP1A1 / 2的蛋白表达和代谢活性降低，因此在NAFLD大鼠中观察到从氯氮平形成诺氯氮平的体外CL _int明显慢于对照组。但是，NAFLD大鼠的氯氮平全身暴露量与对照组相比，静脉内（4 mg / kg）和口服（10 mg / kg）氯氮平暴露量可比。

3. 值得注意的是，norclozapine和AUC的AUC _norclozapine / AUC_氯氮平以下氯氮平静脉内和口服施用比率而在NAFLD大鼠显著增加，因为的结果经由CYP1A1 / 2减慢norclozapine的后续代谢。静脉输注氯氮平后，NAFLD大鼠的氯氮平和去甲氯氮平的稳态脑浓度均显着高于对照组。

4. 在NAFLD大鼠中观察到的氯氮平全身暴露量增加以及氯氮平和甲氧氯氮平的脑部浓度升高，这意味着对已存在或药物诱发的肝脂肪变性患者进行氯氮平的药物治疗尚需进一步研究。