ABSTRACT:The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(؊)-N-methyl-␥-(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 14 C-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, and N-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 (t 1/2 ‫؍‬ 62 h) compared with EM subjects (t 1/2 ‫؍‬ 18 h). In EM subjects, atomoxetine (t 1/2 ‫؍‬ 5 h) and 4-hydroxyatomoxetine-O-glucuronide (t 1/2 ‫؍‬ 7 h) were the principle circulating species, whereas atomoxetine (t 1/2 ‫؍‬ 20 h) and Ndesmethylatomoxetine (t 1/2 ‫؍‬ 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.Atomoxetine hydrochloride (LY139603; formerly known as tomoxetine hydrochloride) is known chemically as (Ϫ)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride. Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other monoamine transporters or receptors (Wong et al., 1982;Gehlert et al., 1993). Atomoxetine is under development as a therapeutic agent for the treatment of attention deficit/hyperactivity disorder in children, adolescents, and adults.Atomoxetine is predominantly metabolized by CYP2D6 (Ring et al., 2002); therefore, its single and multiple dose pharmacokinetics are influenced by the polymorphic expression of this enzyme (Farid et al., 1985). As a result, the pharmacokinetics of atomoxetine appear to have a bimodal distribution with two distinct populations. The enzymatic activity of CYP2D6 is determined by a genetic polymorphism (Evans et al., 1980;Steiner et al., 1988), and is an important source of intersubject variability in metabolism for a number of drugs, including debrisoquine, desipramine, and dextromethorphan (Wolf and Smith, 1999). Mutations or deletion of the CYP2D6 gene results in a mino...

Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration-time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.

For patients with attention-deficit/hyperactivity disorder who have hepatic impairment, dosage adjustment is recommended. Initial target doses should be reduced to 25% and 50% of the normal dose for patients with severe and moderate hepatic impairment, respectively.

No abstract