Cytochrome P450 dependent metabolism of fluindione in vitro in rat and human microsomes and in vivo in rat. - Archive ouverte HAL
Poster De Conférence Année : 2018

Cytochrome P450 dependent metabolism of fluindione in vitro in rat and human microsomes and in vivo in rat.

Résumé

Fluindione (2-(4’fluoro-phenyl)-phenylindan1,3-dione) is an anti-vitamin K (AVK) marketed in 1967 in France and in Luxembourg (1-3). It is still the leading AVK in France in 2016 (around 800.000 patients, 82% of the market). However very little is known on the metabolism of this drug. In order to better understand the pharmacokinetics of this drug (4,5), we started to study the in vitro and in vivo metabolism of fluindione. Thus the incubation of fluindione with rat liver microsomes showed a major metabolite X, having a similar UV spectrum as fluindione, but slighly less polar and a high resolution mass spectrum showing addition of an oxygen atom. Its formation was dependent on NADPH and O2 and was inhibited by benzyl-imidazole, a general cytochrome P450 inhibitor. Semi-preparative incubations of fluindione allowed to get an 1H NMR spectrum showing the presence of 8 non exchangeable protons corresponding to an asymmetric aromatic A ring and an unchanged fluorophenyl. Incubation with human liver microsomes showed the formation of this metabolite X. Use of recombinant P450 showed that CYP1A2, 2B6, 2C9, 2D6, 3A4 and 3A5 could produce this metabolite. CYP2C9 and CYP1A2 had good affinities (less than 30 µM). The chemical synthesis of several candidate metabolites was performed: 2-hydroxy-fluindione, 2-(4’-fluorophenyl)-4-hydroxy-coumarin, 2-(4’-fluorophenyl)-4-hydroxy-isocoumarin (new). X corresponded to none of these candidates. An equimolar mixture of fluindione and 13C labeled fluindione on the aromatic A ring was injected IP in rats (20 mg/kg). Analysis of plasma showed the formation of metabolite X and of two minor metabolites. The first minor one Y as identified to (2-(4’hydroxy-phenyl)-phenyl)-indan1,3-dione formed by defluorination and hydroxylation of the fluorophenyl group (a known metabolic reaction). A second minor metabolite Z in very low amount could be the equivalent of metabolite X with fluorine replaced by hydroxyl. In rat urine the sulfate of X and the sulfate of Z and a trace of Y could be found.In human (10 mg per os) fluindione and metabolite X were detected. Further experiments are ongoing in order to finally identify metabolite X.
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Dates et versions

hal-02348026 , version 1 (08-11-2019)

Identifiants

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Patrick M. Dansette, Assia Hessani, Virginie Siguret, Catherine Boisson-Vidal, Jean-Luc Boucher, et al.. Cytochrome P450 dependent metabolism of fluindione in vitro in rat and human microsomes and in vivo in rat.. MDO-JSSX joint confrerence, Oct 2018, Kanazawa, Japan. ⟨10.13140/RG.2.2.30474.31680⟩. ⟨hal-02348026⟩
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