THE OXIDATIVE-METABOLISM OF METOPROLOL IN HUMAN LIVER-MICROSOMES - INHIBITION BY THE SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Objective: Biotransformation of metoprolol to alpha-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) is mediated by CYP2D6. The selecti ve serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6. The aim was to study in vitro the potential inhibitory effect of SSRIs on metoprolol biotransformation. Methods: Using microsomes from two h uman livers, biotransformation of metoprolol to alpha-hydroxymetoprolo l (HM) and O-demethylmetoprolol (ODM) as a function of the concentrati ons of the SSRIs and of some of their metabolites was studied. Results : The kinetics of the formation of both metabolites are best described by a biphasic enzyme model. The estimated values of V-max and k(M) fo r the high affinity site are for the alpha-hydroxylation in human live r HL-1 32 mu mol mg(-1).min(-1) and 75 mu mol.l(-1) respectively, and in human liver HL-9 39 mu mol mg(-1).min(-1) and 70 mu mol.l(-1) respe ctively; for the O-demethylation in HL-1 131 pmol mg(-1) min(-1) and 9 5 mu mol.l(-1) respectively, and in HL-9 145 pmol mg(-1) min(-1) and 9 4 mu mol.l(-1) respectively. Quinidine is for both pathways a potent i nhibitor of the high-affinity site, with K-i values ranging from 0.03 to 0.18 mu mol.l(-1). Fluoxetine, norfluoxetine and paroxetine are lik ewise potent inhibitors, with K-i values ranging from 0.30 to 2.1 mu m ol.l(-1) fluvoxamine, sertraline, desmethylsertraline, citalopram and desmethylcitalopram are less potent inhibitors, with K-i values above 10 mu mol.l(-1). Conclusion: The rank order of the SSRIs for inhibitio n of metoprolol metabolism is comparable to that reported in the liter ature for other CYP2D6 substrates, with fluoxetine, norfluoxetine and paroxetine being the most potent. These findings need further investig ation to determine their clinical relevance.