Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4
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SHORT COMMUNICATION
Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4 Przemysław J. Danek1 · Agnieszka Basińska‑Ziobroń1 · Jacek Wójcikowski1 · Władysława A. Daniel1 Received: 29 May 2020 / Revised: 24 August 2020 / Accepted: 26 August 2020 © The Author(s) 2020
Abstract Background Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs. Methods The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). 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). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Results The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. Conclusion Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates. Keywords Levomepromazine · Clozapine · Cytochrome P450 · Induction · Human hepatocytes
Introduction Cytochrome P450 (CYP) is one of the largest drug-metabolizing enzyme systems whose expression has significant substrate and tissue specificity. The CYP enzymes are involved in the biotransformation of most drugs and other xenobiotics, and help to eliminate them out of the body [1]. Moreover, CYPs regulate many important life processes, such as the metabolism of melatonin, steroids (e.g., biosynthesis of Jacek Wójcikowski: Deceased. * Władysława A. Daniel nfdaniel@cyf‑kr.edu.pl 1
Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31‑343 Kraków, Poland
estrogen), arachidonic acid, conversion of cholesterol into bile acids and biotransformation of bile acids. Levomepromazine is a typical phenothiazine antipsychotic with sedative/hypnotic, anxiolytic, antiemetic, analgesic and antipsychotic activities. It is used for treating schizophrenia, paranoia, mania, toxic psychosis and mental organic syndromes associated with delirium [2]. Clozapine was the first s
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