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Vol. 297, Issue 3, 1044-1050, June 2001

Identification of the Human Cytochromes P450 Responsible for in Vitro Formation of R- and S-Norfluoxetine

Barbara J. Ring, James A. Eckstein, Jennifer S. Gillespie, Shelly N. Binkley, Mark VandenBranden and Steven A. Wrighton

Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana

The formation of R- and S-norfluoxetine was analyzed in vitro in human liver microsomes. Low apparent Km values for R-norfluoxetine formation of <= 8 µM and S-norfluoxetine of <0.2 µM were determined. R-Norfluoxetine formation rates in a characterized microsomal bank correlated with the catalytic activities for cytochrome P450 (CYP) 2D6, CYP2C9, and CYP2C8. Expressed CYP2C9, CYP2C19, and CYP2D6 formed R-norfluoxetine following incubation with 1 µM R-fluoxetine and exhibited apparent Km values of 9.7, 8.5, and 1.8 µM, respectively. Multivariate correlation analysis identified CYP2C9 and CYP2D6 as significant regressors with R-norfluoxetine formation. Antibodies to the CYP2C subfamily and CYP2D6 each exhibited moderate inhibition of R-norfluoxetine formation. Therefore, CYP2D6 and CYP2C9 contribute to this biotransformation. At pharmacological concentrations of S-fluoxetine, S-norfluoxetine formation rates in the bank of microsomes were found to correlate only with CYP2D6 catalytic activity and only expressed CYP2D6 was found to be capable of forming S-norfluoxetine. Thus, it would appear that both CYP2D6 and CYP2C9 contribute to the formation of R-norfluoxetine, whereas only CYP2D6 is responsible for the conversion to S-norfluoxetine. Since the enantiomers of fluoxetine and norfluoxetine are inhibitors of CYP2D6, upon chronic dosing, the CYP2D6-mediated metabolism of the fluoxetine enantiomers would likely be inhibited, resulting in R-norfluoxetine formation being mediated by CYP2C9 and S-norfluoxetine formation being mediated by multiple high Km enzymes.

0022-3565/01/2973-1044$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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