The cytochrome P450-catalyzed metabolism of levomepromazine: a phenothiazine neuroleptic with a wide spectrum of clinical application

Wójcikowski, Jacek; Basińska, Agnieszka; Daniel, W.A.

doi:10.1016/j.bcp.2014.05.005

Cited by 19 publications

(7 citation statements)

References 33 publications

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“…The role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 in the catalysis of the above-mentioned reactions is negligible (0.1-8%). The results obtained indicate that in case of both chlorpromazine and levomepromazine provide possible pharmacokinetic interactions between these drugs and CYP3A4 substrates (e.g., testosterone, tricyclic antidepressants, and macrolide antibiotics calcium channel blockers), and inhibitors (e.g., erythromycin, ketoconazole, and selective serotonin reuptake inhibitor (SSRI)), or inducers (e.g., carbamazepine, rifampicin) [64].…”

Section: Cytochrome P450 Monooxygenasesmentioning

confidence: 96%

“…Its long half-life allows for administration once a day, and its cost is also beneficial. This compound is a moderate dopamine D 2 receptor antagonist responsible for its antipsychotic activity, as well as α1-adrenoceptor and M1-muscarinic receptors, which are associated with some side effects of this drug (hypotension, sedation, and anticholinergic symptoms) such as the chlorpromazine mentioned above [64].…”

Section: Cytochrome P450 Monooxygenasesmentioning

confidence: 99%

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Biotechnological Methods of Sulfoxidation: Yesterday, Today, Tomorrow

2018

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The production of chiral sulphoxides is an important part of the chemical industry since they have been used not only as pharmaceuticals and pesticides, but also as catalysts or functional materials. The main purpose of this review is to present biotechnological methods for the oxidation of sulfides. The work consists of two parts. In the first part, examples of biosyntransformation of prochiral sulfides using whole cells of bacteria and fungi are discussed. They have more historical significance due to the low predictability of positive results in relation to the workload. In the second part, the main enzymes responsible for sulfoxidation have been characterized such as chloroperoxidase, dioxygenases, cytochrome flavin-dependent monooxygenases, and P450 monooxygenases. Particular emphasis has been placed on the huge variety of cytochrome P450 monooxygenases, and flavin-dependent monooxygenases, which allows for pure sulfoxides enantiomers effectively to be obtained. In the summary, further directions of research on the optimization of enzymatic sulfoxidation are indicated.

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Section: Cytochrome P450 Monooxygenasesmentioning

confidence: 96%

Section: Cytochrome P450 Monooxygenasesmentioning

confidence: 99%

Biotechnological Methods of Sulfoxidation: Yesterday, Today, Tomorrow

2018

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“…Our recent metabolic studies have shown that CYP3A4 is the main isoenzyme responsible for levomepromazine metabolism [4,5]. However, a possible inhibition of human CYP isoenzymes by levomepromazine has not been fully investigated so far.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human cytochrome P450 isoenzymes by a phenothiazine neuroleptic levomepromazine: An in vitro study

Basińska-Ziobroń

Daniel

Wójcikowski

2015

Pharmacological Reports

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The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K(i) values are below or close to the presumed concentration range for levomepromazine in the liver in vivo. Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs.

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“…Although there are some experimental data suggesting a possibility of induction of CYP isoforms by typical and atypical neuroleptics [4], the ability of levomepromazine and clozapine to induce human CYPs has not been studied so far. Levomepromazine is chiefly metabolized by CYP3A4 via 5-sulfoxidation and N-demethylation [5], while clozapine is mainly biotransformed by CYP1A2 via N-demethylation and by CYP3A4 via N-oxidation [6].…”

Section: Introductionmentioning

confidence: 99%

Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4

et al. 2020

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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.

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The cytochrome P450-catalyzed metabolism of levomepromazine: a phenothiazine neuroleptic with a wide spectrum of clinical application

Cited by 19 publications

References 33 publications

Biotechnological Methods of Sulfoxidation: Yesterday, Today, Tomorrow

Biotechnological Methods of Sulfoxidation: Yesterday, Today, Tomorrow

Inhibition of human cytochrome P450 isoenzymes by a phenothiazine neuroleptic levomepromazine: An in vitro study

Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4

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