CYP2D6 is involved in the O-demethylation metabolic pathway of venlafaxine in humans. In this study, we investigated whether this isozyme is stereoselective. Plasma samples from seven CYP2D6 extensive metabolizers (EMs) and five CYP2D6 poor metabolizers (PMs), collected during a period without and with coadministration of quinidine, were analysed. Subjects were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1 week apart); once alone and once during the concomitant administration of quinidine sulphate every 12 h. Blood and urine samples were collected under steady-state conditions over one dosing interval (12 h). The present results show that, although CYP2D6 catalyses the O-demethylation of both enantiomers of venlafaxine, it displays a marked stereoselectivity towards the (R)-enantiomer. The oral clearance of (R)-venlafaxine was found to be nine-fold higher in EMs compared to PMs [median (range) 173 (29-611) l/h versus 20 (16-24) l/h, P < 0.005], while it was two-fold higher for (S)-venlafaxine [73 (32-130) l/h versus 37 (21-44) l/h, P < 0.05]. In EMs, quinidine decreased (R)- and (S)-venlafaxine oral clearance by 12-fold ( 0.05) and four-fold ( 0.05), respectively. In contrast, quinidine did not have any effects on renal clearance of (R)-venlafaxine [4 (2-10) l/h for venlafaxine alone versus 5 (0.6-7) l/h for venlafaxine + quinidine] and of (S)-venlafaxine [4 (1-7) l/h for venlafaxine alone versus 3 (0.4-6) l/h for venlafaxine + quinidine]. The coadministration of quinidine to EMs resulted in an almost complete inhibition of the partial metabolic clearance of (R)-venlafaxine to O-demethylated metabolites [127 (10-493) l/h down to 1 (0.1-3) l/h, 0.05], while a seven-fold reduction was measured for (S)-venlafaxine [47 (14-94) l/h versus 7 (1-19) l/h, 0.05]. In PMs, coadministration of quinidine did not significantly change oral clearance and partial metabolic clearance of (R)- and (S)-venlafaxine to its various metabolites. In contrast, data obtained on the partial metabolic clearance of (R)- and (S)-venlafaxine to N-demethylated metabolites, a reaction which is mediated by CYP3A4, suggest a lack of stereoselectivity of this enzyme.