Przejdź do zawartości
Merck

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

Biochemical pharmacology (2014-05-21)
Jacek Wójcikowski, Agnieszka Basińska, Władysława A Daniel
ABSTRAKT

The aim of the present study was to identify cytochrome P450 isoenzymes (CYPs) involved in the 5-sulfoxidation and N-demethylation of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. Experiments were performed in vitro using cDNA-expressed human CYP isoforms (Supersomes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The obtained results indicate that CYP3A4 is the main isoform responsible for levomepromazine 5-sulfoxidation (72%) and N-demethylation (78%) at a therapeutic concentration of the drug (10μM). CYP1A2 contributes to a lesser degree to levomepromazine 5-sulfoxidation (20%). The role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 in catalyzing the above-mentioned reactions is negligible (0.1-8%). Moreover, at a higher, toxicological concentration of the neuroleptic (100μM), the relative contribution of CYP1A2 to levomepromazine metabolism visibly increases (from 20% to 28% for 5-sufoxidation, and from 8% to 32% for N-demethylation), while the role of CYP3A4 significantly decreases (from 72% to 59% for 5-sulfoxidation, and from 78% to 47% for N-demethylation). The obtained results indicate that the catalysis of levomepromazine 5-sulfoxidation and N-demethylation in humans shows a strict CYP3A4 preference, especially at a therapeutic drug concentration. Hence pharmacokinetic interactions involving levomepromazine and CYP3A4 substrates (e.g. tricyclic antidepressants, calcium channel antagonists, macrolide antibiotics, testosterone), inhibitors (e.g. ketoconazole, erythromycin, SSRIs) or inducers (e.g. rifampicin, carbamazepine) are likely to occur.

MATERIAŁY
Numer produktu
Marka
Opis produktu

Sigma-Aldrich
Potassium carbonate, puriss. p.a., ACS reagent, anhydrous, ≥99.0% (T)
Sigma-Aldrich
Potassium carbonate, BioXtra, ≥99.0%
Sigma-Aldrich
Sodium hydroxide-16O solution, 20 wt. % in H216O, 99.9 atom % 16O
Sigma-Aldrich
Potassium carbonate, anhydrous, powder, 99.99% trace metals basis
Supelco
Fumaric acid, certified reference material, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
Sigma-Aldrich
Quinidine, crystallized, ≥98.0% (dried material, NT)
Sigma-Aldrich
Fumaric acid, ≥99.0% (T)
Sigma-Aldrich
Potassium carbonate, 99.995% trace metals basis
Sigma-Aldrich
Potassium carbonate, BioUltra, anhydrous, ≥99.0% (T)
Sigma-Aldrich
Fumaric acid, FCC, FG
Sigma-Aldrich
Potassium carbonate, meets USP testing specifications
Sigma-Aldrich
Furafylline, ≥98% (HPLC)
Sigma-Aldrich
Quinidine, anhydrous
Fumaric acid, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Potassium carbonate, ACS reagent, ≥99.0%
Sigma-Aldrich
Potassium carbonate, anhydrous, free-flowing, Redi-Dri, ACS reagent, ≥99%
Sigma-Aldrich
Potassium carbonate, ReagentPlus®, 99%
Supelco
Fumaric Acid, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Potassium carbonate, reagent grade, ≥98%, powder, −325 mesh
Supelco
Sodium hydroxide concentrate, 0.1 M NaOH in water (0.1N), Eluent concentrate for IC
Sigma-Aldrich
Ammonia-14N, 99.99 atom % 14N
Sigma-Aldrich
Ammonia solution, 4 M in methanol
Sigma-Aldrich
Ammonia, puriss., anhydrous, ≥99.95%
Sigma-Aldrich
3-Ethyl-2,4-pentanedione, mixture of tautomers, 98%
Sigma-Aldrich
Sodium hydroxide, BioUltra, for luminescence, ≥98.0% (T), pellets
Supelco
Sodium hydroxide solution, 49-51% in water, eluent for IC
Sigma-Aldrich
Sodium hydroxide solution, BioUltra, for molecular biology, 10 M in H2O
Sigma-Aldrich
Sodium hydroxide solution, 1.0 N, BioReagent, suitable for cell culture
Sigma-Aldrich
Sodium hydroxide, ultra dry, powder or crystals, 99.99% trace metals basis
Sigma-Aldrich
Sodium hydroxide, reagent grade, 97%, flakes