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

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 -desethylreboxetine, whereas inhibitors selective for other CYP enzymes did not inhibit reboxetine metabolism, 2) formation of O -desethylreboxetine correlated ( r 2 = 0.99; p 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.