TY - JOUR T1 - Identification of the Human Cytochromes P450 Responsible for Atomoxetine Metabolism JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 319 LP - 323 DO - 10.1124/dmd.30.3.319 VL - 30 IS - 3 AU - Barbara J. Ring AU - Jennifer S. Gillespie AU - James A. Eckstein AU - Steven A. Wrighton Y1 - 2002/03/01 UR - http://dmd.aspetjournals.org/content/30/3/319.abstract N2 - Studies were performed to determine the human enzymes responsible for the biotransformation of atomoxetine to its major metabolite, 4-hydroxyatomoxetine, and to a minor metabolite,N-desmethylatomoxetine. Utilizing human liver microsomes containing a full complement of cytochrome P450 (P450) enzymes, averageKm and CLint values of 2.3 μM and 103 μl/min/mg, respectively, were obtained for 4-hydroxyatomoxetine formation. Microsomal samples deficient in CYP2D6 exhibited average apparent Km and CLint values of 149 μM and 0.2 μl/min/mg, respectively. In a human liver bank characterized for P450 content, formation of 4-hydroxyatomoxetine correlated only to CYP2D6 activity. Of nine expressed P450s examined, 4-hydroxyatomoxetine was formed at a rate 475-fold greater by CYP2D6 compared with the other P450s. These results demonstrate that CYP2D6 is the enzyme primarily responsible for the formation of 4-hydroxyatomoxetine. Multiple P450s were found to be capable of forming 4-hydroxyatomoxetine when CYP2D6 was not expressed. However, the efficiency at which these enzymes perform this biotransformation is reduced compared with CYP2D6. The formation of the minor metabolite N-desmethylatomoxetine exhibited average Km and CLint values of 83 μM and 0.8 μl/min/mg, respectively. Utilizing studies similar to those outlined above, CYP2C19 was identified as the primary enzyme responsible for the biotransformation of atomoxetine toN-desmethylatomoxetine. In summary, CYP2D6 was found to be the primary P450 responsible for the formation of the major oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine. Furthermore, these studies indicate that in patients with compromised CYP2D6 activity, multiple low-affinity enzymes will participate in the formation of 4-hydroxyatomoxetine. Therefore, coadministration of P450 inhibitors to poor metabolizers of CYP2D6 substrates would not be predicted to decrease the clearance of atomoxetine in these individuals. The American Society for Pharmacology and Experimental Therapeutics ER -