title: Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites.
abstract: To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC-MS/MS. For atomoxetine, the Cmax, AUC0-∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0-∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0-∞ was not different between these groups. The Cmax, AUC0-∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
authors.forename: Ji-Yeong
authors.initials: JY
authors.lastname: Byeon
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: National Institute of Food and Drug Safety Evaluation, MFDS, Cheongwon-Gun, 363-951, Republic of Korea.
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Na
authors.affiliation: Department of Dental Hygiene, Hanseo University, Seosan, 356-706, Republic of Korea.
authors.forename: Jong-Hwa
authors.initials: JH
authors.lastname: Jang
authors.affiliation: National Institute of Food and Drug Safety Evaluation, MFDS, Cheongwon-Gun, 363-951, Republic of Korea.
authors.forename: Se-Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.|College of Pharmacy, Dankook University, Cheonan, 330-714, Republic of Korea.
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Keimyung University, Daegu, 704-701, Republic of Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Bae
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
authors.forename: In Su
authors.initials: IS
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.affiliation: National Institute of Food and Drug Safety Evaluation, MFDS, Cheongwon-Gun, 363-951, Republic of Korea.
authors.forename: Myeon-Woo
authors.initials: MW
authors.lastname: Chung
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea. sylee@skku.ac.kr.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics; D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D000069445:Atomoxetine Hydrochloride / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D010636:Phenols / Q000493:pharmacokinetics*; D010647:Phenyl Ethers / Q000493:pharmacokinetics*; D011437:Propylamines / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D010636:Phenols; D010647:Phenyl Ethers; D011437:Propylamines; C454680:N-desmethylatomoxetine; D000069445:Atomoxetine Hydrochloride; C454679:4-hydroxyatomoxetine; D019389:Cytochrome P-450 CYP2D6
keywords: 4-hydroxyatomoxetine; Atomoxetine; CYP2D6*10; Pharmacokinetics