title: Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes.
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 microM, 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 <.001) with CYP3A-selective testosterone 6-beta-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 microM, 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.
authors.affiliation: Department of Drug Metabolism, Pharmacia & Upjohn, Kalamazoo, Michigan 49007, USA. larry.c.wienkers@am.pnu.com
authors.forename: L C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: C
authors.initials: C
authors.lastname: Allievi
authors.forename: M J
authors.initials: MJ
authors.lastname: Hauer
authors.forename: M A
authors.initials: MA
authors.lastname: Wynalda
mesh_terms: D000928:Antidepressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D009025:Morpholines / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077593:Reboxetine; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000928:Antidepressive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009025:Morpholines; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D000077593:Reboxetine