title: Effects of CYP2C19 genetic polymorphisms on atomoxetine pharmacokinetics.
abstract: Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit/hyperactivity disorder. Atomoxetine metabolism is mediated by CYP2D6 and CYP2C19. This study aimed to investigate the effect of the CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. A single 40-mg oral dose of atomoxetine was administered to 40 subjects with different CYP2C19 genotypes (all participants carried the CYP2D6*1/*10 genotype). Concentrations of atomoxetine and its metabolites were analyzed using high-performance liquid chromatography with tandem mass spectrometry in plasma samples that were collected up to 24 hours after drug intake. For atomoxetine, the CYP2C19 poor metabolizer (PM) group showed significantly increased maximum plasma concentration and AUC0-∞ (area under the plasma concentration-time curve from 0 to infinity) and decreased apparent oral clearance compared with samples of the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM) groups (P < 0.001 for all). The half-life of atomoxetine in the CYP2C19PM group was also significantly longer than in the other genotype groups (P < 0.01 for CYP2C19EM and P < 0.05 for CYP2C19IM groups). The maximum plasma concentration and AUC 0-∞ of 4-hydroxyatomoxetine were significantly higher in the CYP2C19PM group compared with those in the CYP2C19EM and IM groups (P < 0.001 for CYP2C19EM and P < 0.05 for CYP2C19IM, respectively), whereas the corresponding values for N-desmethylatomoxetine in the CYP2C19PM group were significantly lower than those in the 2 genotype groups (P < 0.001 for both genotype groups). These results suggest that the genetic polymorphisms of CYP2C19 significantly affect the pharmacokinetics of atomoxetine.
authors.affiliation: From the *School of Pharmacy, Sungkyunkwan University, Suwon; †College of Pharmacy, Keimyung University, Daegu; and ‡College of Pharmacy, Dankook University, Cheonan, Republic of Korea.
authors.forename: Chang-Ik
authors.initials: CI
authors.lastname: Choi
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Bae
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Lee
authors.forename: Hye-In
authors.initials: HI
authors.lastname: Lee
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D000069445:Atomoxetine Hydrochloride; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010597:Pharmacogenetics; D010636:Phenols / Q000097:blood; D010641:Phenotype; D010647:Phenyl Ethers / Q000097:blood; D011110:Polymorphism, Genetic; D011437:Propylamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D018759:Adrenergic Uptake Inhibitors; D010636:Phenols; D010647:Phenyl Ethers; D011437:Propylamines; C454680:N-desmethylatomoxetine; D000069445:Atomoxetine Hydrochloride; C454679:4-hydroxyatomoxetine; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19