Asenapine and iloperidone decrease the expression of major cytochrome P450 enzymes CYP1A2 and CYP3A4 in human hepatocytes. A significance for drug-drug interactions during combined therapy

Abstract

Antipsychotics are often used in combination with other psychotropic drugs to treat a variety of psychiatric disorders, as well as in combination with other drugs taken by patients with co-morbidities. When these drugs are combined, the potential for drug-drug interaction increases, leading to side-effects, in addition to the predicted increase in effectiveness. The present study aimed at examining the effects of the three atypical neuroleptics asenapine, lurasidone and iloperidone on cytochrome P450 (CYP) expression in the human liver.The study was carried out on cryopreserved human hepatocytes. The hepatotoxicity of the tested drugs was assessed after exposure to the neuroleptics (LDH cytotoxicity assay). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4′-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). Parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes.Asenapine significantly decreased the mRNA level and activity of CYP1A2, while iloperidone potently diminished the mRNA level and activity of CYP3A4 in the cultures of human hepatocytes. Lurasidone did not affect the expression and activity of any of the investigated human CYP enzymes.The presented findings may have clinical implications for the prediction of potential drug-drug interactions involving the asenapine-induced inhibition of metabolism of CYP1A2 substrates (e.g. caffeine, theophylline, melatonin, tricyclic antidepressants, phenacetin, propranolol) and iloperidone-induced inhibition of CYP3A4 substrates (e.g. antidepressants, benzodiazepines, atorvastatin, macrolide antibiotics, calcium channel antagonists).