Titre du document / Document title

Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes

Auteur(s) / Author(s)

WIENKERS L. C. ⁽¹⁾ ; ALLIEVI C. ⁽¹⁾ ; HAUER M. J. ⁽¹⁾ ; WYNALDA M. A. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Drug Metabolism, Pharmacia & Upjohn, Kalamazoo, Michigan, ETATS-UNIS

Résumé / Abstract

In vitro studies were conducted to identify the hepatic cytochrome P-450 (CYP) enzymes responsible for the oxidative metabolism of the individual enantiomers of reboxetine. In human liver microsomes, each reboxetine enantiomer was metabolized to one primary metabolite, O-desethylreboxetine, and three minor metabolites, two arising via oxidation of the ethoxy aromatic ring and a third yet unidentified metabolite. Over a concentration range of 2 to 200 μM, the rate O-desethylreboxetine formation for either enantiomer conformed to monophasic Michaelis-Menten kinetics. Evidence for a principal role of CYP3A in the formation of O-desethylreboxetine for (S,S)-reboxetine and (R,R)-reboxetine was based on the results from the following studies: 1) inhibition of CYP3A activity by ketoconazole markedly decreased the formation of O-desethyireboxetine, whereas inhibitors selective for other CYP enzymes did not inhibit reboxetine metabolism, 2) formation of O-desethylreboxetine correlated (r² = 0.99; p <.001) with CYP3A-selective testosterone 6-β-hydroxylase activity across a population of human livers (n = 14). Consistent with inhibition and correlation data, O-desethylreboxetine formation was only detectable in incubations using microsomes prepared from a Baculovirus-insect cell line expressing CYP3A4. Furthermore, the apparent K_M for the O-desethylation of reboxetine in cDNA CYP3A4 microsomes was similar to the affinity constants determined in human liver microsomes. In addition, (S,S)-reboxetine and (R,R)-reboxetine were found to be competitive inhibitors of CYP2D6 and CYP3A4 (K_i = 2.5 and 11 μM, respectively). Based on the results of the study, it is concluded that the metabolism of both reboxetine enantiomers in humans is principally mediated via CYP3A.

Revue / Journal Title

Drug metabolism and disposition   ISSN 0090-9556   CODEN DMDSAI 

Source / Source

1999, vol. 27, n^o11, pp. 1334-1340 (32 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, ETATS-UNIS  (1973) (Revue)

Mots-clés anglais / English Keywords

Reboxetine ; Antidepressant agent ; Psychotropic ; Metabolism ; Stereospecificity ; Enantiomer ; Human ; Liver ; Digestive system ; In vitro ; Microsome ; Isozyme ; Cytochrome P450 ; Drug-metabolizing enzyme ; Unspecific monooxygenase ; Enzyme ; Oxidoreductases ;

Mots-clés français / French Keywords

Réboxétine ; Antidépresseur ; Psychotrope ; Métabolisme ; Stéréospécificité ; Enantiomère ; Homme ; Foie ; Appareil digestif ; In vitro ; Microsome ; Isozyme ; Cytochrome P450 ; Drug-metabolizing enzyme ; Unspecific monooxygenase ; Cytochrome CYP3A ; Enzyme ; Oxidoreductases ;

Mots-clés espagnols / Spanish Keywords

Reboxetina ; Antidepresor ; Psicotropo ; Metabolismo ; Estereoespecificidad ; Enantiómero ; Hombre ; Hígado ; Aparato digestivo ; In vitro ; Microsoma ; Isozima ; Citocromo P450 ; Drug-metabolizing enzyme ; Unspecific monooxygenase ; Enzima ; Oxidoreductases ;

Localisation / Location

INIST-CNRS, Cote INIST : 16545, 35400008033665.0150