TY - JOUR T1 - Disposition and Metabolic Fate of Atomoxetine Hydrochloride: The Role of CYP2D6 in Human Disposition and Metabolism JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 98 LP - 107 DO - 10.1124/dmd.31.1.98 VL - 31 IS - 1 AU - John-Michael Sauer AU - G. Douglas Ponsler AU - Edward L. Mattiuz AU - Amanda J. Long AU - Jennifer W. Witcher AU - Holly R. Thomasson AU - Karl A. Desante Y1 - 2003/01/01 UR - http://dmd.aspetjournals.org/content/31/1/98.abstract N2 - The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(−)-N-methyl-γ-(2-methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented following both single and multiple doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the overall disposition and metabolism of a 20-mg dose of 14C-atomoxetine was evaluated in CYP2D6 extensive metabolizer (EM; n = 4) and poor metabolizer (PM;n = 3) subjects under steady-state conditions. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the preponderance of radioactivity being excreted into the urine. In EM subjects, the majority of the radioactive dose was excreted within 24 h, whereas in PM subjects the majority of the dose was excreted by 72 h. The biotransformation of atomoxetine was similar in all subjects undergoing aromatic ring hydroxylation, benzylic oxidation, andN-demethylation with no CYP2D6 phenotype-specific metabolites. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged in PM subjects (t1/2 = 62 h) compared with EM subjects (t1/2 = 18 h). In EM subjects, atomoxetine (t1/2 = 5 h) and 4-hydroxyatomoxetine-O-glucuronide (t1/2 = 7 h) were the principle circulating species, whereas atomoxetine (t1/2 = 20 h) andN-desmethylatomoxetine (t1/2 = 33 h) were the principle circulating species in PM subjects. Although differences were observed in the excretion and relative amounts of metabolites formed, the primary difference observed between EM and PM subjects was the rate at which atomoxetine was biotransformed to 4-hydroxyatomoxetine. The American Society for Pharmacology and Experimental Therapeutics ER -