Effects of the CYP2D610 allele on the pharmacokinetics of atomoxetine and its metabolites

• Published in: Archives of pharmacal research Vol. 38; no. 11; pp. 2083 - 2091
• Main Authors: Byeon, Ji-Yeong, Kim, Young-Hoon, Na, Han-Sung, Jang, Jong-Hwa, Kim, Se-Hyung, Lee, Yun-Jeong, Bae, Jung-Woo, Kim, In Su, Jang, Choon-Gon, Chung, Myeon-Woo, Lee, Seok-Yong
• Format: Journal Article
• Language: English
• Published: Seoul Pharmaceutical Society of Korea 01.11.2015; 대한약학회
• Subjects: Adrenergic Uptake Inhibitors - pharmacokinetics; Adult; Alleles; Area Under Curve; Atomoxetine Hydrochloride - pharmacokinetics; Chromatography, Liquid; Cytochrome P-450 CYP2D6 - genetics; Genotype; Half-Life; Humans; Male; Medicine; metabolites; pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Phenols - pharmacokinetics; Phenyl Ethers - pharmacokinetics; Propylamines - pharmacokinetics; Research Article; risk; Tandem Mass Spectrometry; Young Adult; 약학; Atomoxetine; 4-hydroxyatomoxetine; Pharmacokinetics; CYP2D610
• ISSN: 0253-6269; 1976-3786; 1976-3786
• DOI: 10.1007/s12272-015-0646-z

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.