Metoprolol-paroxetine interaction in human liver microsomes: Stereoselective aspects and prediction of the in vivo interaction

This study in human liver microsomes was undertaken to establish whether pa roxetine stereoselectively inhibits the oxidative metabolism of metoprolol in vitro, and whether the in vivo observed magnitude of the paroxetine-meto prolol interaction was predictable from these in vitro data. Two distinct a pproaches were used: inhibitory effect of paroxetine on 1) the formation of alpha -hydroxymetoprolol and O-desmethylmetoprolol from the individual met oprolol enantiomers and 2) on the depletion of the enantiomers from the inc ubation mixture. Nonspecific binding of both metoprolol and paroxetine to h uman liver microsomes was also investigated. Whereas metoprolol displayed n egligible binding, paroxetine was extensively bound to microsomal proteins. This was taken into account in order to obtain unbiased K-i values and unb ound concentrations of paroxetine. In the substrate depletion experiments, the intrinsic clearance (CLint)of (R)-metoprolol was larger than that of (S )-metoprolol. Paroxetine caused a concentration-dependent decrease in CLint of both enantiomers and abolished the stereoselectivity. In the metabolite formation experiments paroxetine did not stereoselectively affect alpha -h ydroxylation, but preferentially inhibited the O-demethylation of the (R)-e nantiomer versus the (S)-enantiomer. The use of unbound paroxetine concentr ations in the two in vitro methods yielded comparable predicted increases i n area under the curve (1.7-1.9 and 2.2-2.5 for (S)- and (R)-metoprolol, re spectively) but underestimated the in vivo observed changes of about 7- and 10-fold, respectively. In conclusion, this study showed that paroxetine ab olishes the stereoselective metabolism of metoprolol due to a stereoselecti ve inhibition of the O-demethylation toward (R)-metoprolol. Furthermore, th e extent of the in vivo metoprolol-paroxetine interaction was substantially underestimated by either one of the two in vitro approaches used when a co mpetitive mechanism was assumed.