title: Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.
abstract: Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.
authors: 1 Laboratory of Pharmacogenomics and Pharmacokinetic Research, Subei People's Hospital, Yangzhou University , Yangzhou, Jiangsu, China .
authors: Guo
authors: G
authors: Yu
authors: 2 Center for Drug Clinical Research, Shanghai University of Chinese Medicine , Shanghai, China .
authors: Guo-Fu
authors: GF
authors: Li
authors: 3 Department of Pharmacotherapy and Translational Research, University of Florida , Gainesville, Florida.|4 Center for Pharmacogenomics, University of Florida , Gainesville, Florida.
authors: John S
authors: JS
authors: Markowitz
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000367:Age Factors; D000069445:Atomoxetine Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6