Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers

Plasma concentrations of the enantiomers of fluoxetine (FLX) and norfluoxet ine (NFLX) were measured at days 7, 14, and 23 of oral administration of 20 mg of racemic fluoxetine in 11 patients who were comedicated with risperid one, Eight patients were genotyped as being cytochrome P4502D6 extensive me tabolizers (EMs) and three as cytochrome P4502D6 poor metabolizers (PMs), N o statistically significant differences were calculated between EMs and PMs in the concentrations of (R)-FLX and (R)-NFLX for all days examined (day 2 3, mean +/- SD for (R)-FLX and (R)-NFLX in EMs, 16 +/- 5 and 29 +/- 20 ng/m L, respectively; in PMs, 16 +/- 1 and 20 +/- 2 ng/mL, respectively), Howeve r, concentrations of (S)-FLX and (S)-NFLX were higher and lower, respective ly, in PMs as compared with EMs (day 7, p = 0.037 and p = 0.036; day 14, p = 0.014 and p = 0.014; day 23, p = 0.068 and p = 0.038), On day 23, mean (S )-FLX and (S)-NFLX in EMs were (mean +/- SD) 39 +/- 26 and 63 +/- 26 ng/mL, and in PMs they were 88 +/- 7 and 19 +/- 2 ng/mL, This study confirms the results of the single-dose studies showing that CYP2D6 is involved in the d emethylation of FLX to NFLX, with a stereoselectivity toward the (S)-enanti omer. The data also clearly show that the CYP2D6 genotype has an important influence on the concentrations of the (S)- but not of the (R)-enantiomer o f FLX and NFLX after multiple doses.