clozapine and Liver-Diseases

Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.

Topics: Animals; Antioxidants; Antipsychotic Agents; Clozapine; Imidazoles; Indoles; Liver; Liver Diseases; Male; Piperazines; Rats; Rats, Wistar; Thiazoles

Physiologically based pharmacokinetic (PBPK) modeling permits clinical scientists to reduce practical constraints for clinical trials on patients with special diseases. In this study, simulations were carried out to validate the pharmacokinetic parameters of clozapine and sildenafil using Simcyp. A full PBPK model was built in the simulator for clozapine and sildenafil based on physicochemical properties and observed clinical results. The model used was Advanced, Dissolution, Absorption and Metabolism (ADAM) for both drugs.. The PBPK model adequately predicted the pharmacokinetic parameters of clozapine and sildenafil for the healthy adult population. In the simulation results, the bioavailability of both drugs was remarkably raised in both renal and hepatic impairment in young and elderly populations.. PBPK modeling could be helpful in the investigation and comparison of the pharmacokinetics in populations with specific disease conditions.

Topics: Adult; Clozapine; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Models, Biological; Sildenafil Citrate; Young Adult

Topics: Adult; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Liver Diseases; Male; Seizures