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.

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

“…In Chinese subjects, homozygous CYP2D6*10 subjects had, on average, a two-fold higher systemic exposure than the heterozygous CYP2D6*10 and the homozygous CYP2D6*1 subjects (Table 3), as a result of 50% reduction in oral clearance (Cui et al 2007). Likewise, systemic atomoxetine exposure in Korean CYP2D6*10/*10 individuals was approximately threefold greater than that observed in Korean CYP2D6*wt/*wt (*wt = *1 or *2) and *wt/*10 subjects (Byeon et al 2015). Atomoxetine circulates principally in the plasma of CYP2D6 EMs as the parent drug and 4-hydroxyatomoxetine-O-glucuronide metabolite; in PMs, however, the most abundant species are the parent compound and the N-desmethylatomoxetine metabolite.…”

“…However, neither the predictive methods nor the actual input data used to generate these predictions were provided in that report (Trzepacz et al 2008). Several studies have directly compared the total and peak atomoxetine exposures in homozygous CYP2D6*10 subjects with other CYP2D6 EM subjects (Cui et al 2007;Matsui et al 2012;Byeon et al 2015). As presented within Table 3, an approximately two-fold higher AUC was observed in the homozygous CYP2D6*10 Japanese subjects than in the CYP2D6*1/*1, *1/*2, *1/*10 and *2/*10 subjects (Matsui et al 2012).…”

Polymorphisms in Serotonergic Pathways Influence the Outcome of Antidepressant Therapy in Psychiatric Inpatients

“…"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. 190 " "Poor metabolizers had higher frequencies of dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. 191 " [189][190][191] Cytochrome P450 2D6 genotype affects the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects: comparison of traditional phenotype and activity score systems http://www.ncbi.nlm.nih.gov/pubmed/25967538 192 "The pharmacokinetics of controlled-release paroxetine after a single administration was affected by CYP2D6 polymorphisms.…”

Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

“…In order to improve the credibility of our experiment, CYP2D6.2 and CYP2D6.10, two typical variants, served as the positive controls for the functional analyses. CYP2D6*10 is the most common allele in Asians, occurring in 42.86% of the Chinese Han population 20,25. Several functional analyses have been shown that CYP2D6.10 has higher K m , lower V max and behave with the least V max /K m values for dextromethorphan, bufuralol, nortriptyline, atomoxetine, and debrisoquine in vitro 21,25…”