Effects of CYP2C19 genetic polymorphism on the disposition of atomoxetine and its major metabolites

Purpose: Atomoxetine, a selective norepinephrine receptor inhibitor (SNRI), is used for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. The  metabolism of atomoxetine is primarily via the major three pathways; aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. CYP2C19, a highly polymorphic drug metabolizing enzyme, is mainly responsible for the atomoxetine N-demethylation. We investigated the effects of CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its major metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (N-DAT).

Methods: Nineteen subjects were selected and they were divided into two different groups according to CYP2C19 genotype, CYP2C19EM (CYP2C19*1/*1, n=12) and CYP2C19PM (CYP2C19*2/*2 or CYP2C19*2/*3, n=7). After overnight fasting, each subject received a single oral dose of 40 mg atomoxetine. Blood samples were collected up to 24 hr after drug intake, and plasma concentrations of atomoxetine and its metabolites were determined by a validated LC-MS/MS analytical method.

Results: C_max and AUC_inf of NDAT in CYP2C19PM group were significantly lower than those in CYP2C19EM group (all P<0.0001). AUC_inf of NDAT in CYP2C19EM and CYP2C19PM groups were 82.0 ± 20.3 ng·hr/mL and 31.0 ± 10.3 ng·hr/mL, respectively. Other parameters of NDAT were not significantly different between two groups. Also, there were no significant differences in the overall pharmacokinetic parameters of atomoxetine and 4-HAT between two genotype groups.

Conclusion: CYP2C19 genetic polymorphism has an impact on the pharmacokinetics of N-desmethylatomoxetine, an inactive metabolite of atomoxetine. The clinical implication of these observations is likely to be little.