RT Journal Article
SR Electronic
T1 Differential Time- and NADPH-Dependent Inhibition of CYP2C19 by Enantiomers of Fluoxetine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 695
OP 698
DO 10.1124/dmd.108.025726
VO 37
IS 4
A1 David M. Stresser
A1 Andrew K. Mason
A1 Elke S. Perloff
A1 Thuy Ho
A1 Charles L. Crespi
A1 Andre A. Dandeneau
A1 Ling Morgan
A1 Shangara S. Dehal
YR 2009
UL http://dmd.aspetjournals.org/content/37/4/695.abstract
AB Fluoxetine [±-N-methyl-3-phenyl-3-[(α, α, (-trifluoro-p-tolyl)oxy]-propylamine)] a selective serotonin reuptake inhibitor, is widely used in treating depression and other serotonin-dependent disease conditions. Racemic, (R)- and (S)-fluoxetine are potent reversible inhibitors of CYP2D6, and the racemate has been shown to be a mechanism-based inhibitor of CYP3A4. Racemic fluoxetine also demonstrates time- and concentration-dependent inhibition of CYP2C19 catalytic activity in vitro. In this study, we compared fluoxetine, its (R)- and (S)-enantiomers, ticlopidine, and S-benzylnirvanol as potential time-dependent inhibitors of human liver microsomal CYP2C19. In a reversible inhibition protocol (30 min preincubation with liver microsomes without NADPH), we found (R)-, (S)- and racemic fluoxetine to be moderate inhibitors with IC50 values of 21, 93, and 27 μM, respectively. However, when the preincubation was supplemented with NADPH, IC50 values shifted to 4.0, 3.4, and 3.0 μM, respectively resulting in IC50 shifts of 5.2-, 28-, and 9.3-fold. Ticlopidine showed a 1.8-fold shift in IC50 value, and S-benzylnirvanol shifted right (0.41-fold shift). Follow-up KI and kinact determinations with fluoxetine confirmed time-dependent inhibition [KI values of 6.5, 47, and 14 μM; kinact values of 0.023, 0.085, 0.030 min–1 for (R)-, (S)-, and racemate, respectively]. Although the (S)-isomer exhibits a much lower affinity for CYP2C19 inactivation relative to the (R)-enantiomer, it exhibits a more rapid rate of inactivation. Racemic norfluoxetine exhibited an 11-fold shift (18–1.5 μM) in IC50 value, suggesting that conversion of fluoxetine to this metabolite represents a metabolic pathway leading to time-dependent inhibition. These data provide an improved understanding of the drug-interaction potential of fluoxetine. The American Society for Pharmacology and Experimental Therapeutics