Determination of atomoxetine metabolites in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study

Byeon

et al. 2018

Sci Rep

Self Cite

Atomoxetine is a norepinephrine reuptake inhibitor indicated in the treatment of attention-deficit/hyperactivity disorder. It is primarily metabolized by CYP2D6 to its equipotent metabolite, 4-hydroxyatomoxetine, which promptly undergoes further glucuronidation to an inactive 4-HAT-O-glucuronide. Clinical trials have shown that decreased CYP2D6 activity leads to substantially elevated atomoxetine exposure and increase in adverse reactions. The aim of this study was to to develop a pharmacologically based pharmacokinetic (PBPK) model of atomoxetine in different CYP2D6 genotypes. A single 20 mg dose of atomoxetine was given to 19 healthy Korean individuals with CYP2D6*wt/*wt (*wt = *1 or *2) or CYP2D6*10/*10 genotype. Based on the results of this pharmacokinetic study, a PBPK model for CYP2D6*wt/*wt individuals was developed. This model was scaled to those with CYP2D6*10/*10 genotype, as well as CYP2D6 poor metabolisers. We validated this model by comparing the predicted pharmacokinetic parameters with diverse results from the literature. The presented PBPK model describes the pharmacokinetics after single and repeated oral atomoxetine doses with regard to CYP2D6 genotype and phenotype. This model could be utilized for identification of appropriate dosages of atomoxetine in patients with reduced CYP2D6 activity to minimize the adverse events, and to enable personalised medicine.

Section: Methodsmentioning

confidence: 99%

Physiologically based pharmacokinetic modelling of atomoxetine with regard to CYP2D6 genotypes

Byeon

et al. 2018

Sci Rep

Self Cite

Journal of Clinical Psychopharmacology

“…15,16 Concentration ranges of the calibration curves for atomoxetine, 4-HAT, and NAT were 1 to 750, 0.05 to 20, and 0.1 to 20 ng/mL, respectively. The mean accuracies of atomoxetine, 4-HAT, and NAT were 93.5% to 101.7%, 99.4% to 102.1%, and 97.0% to 99.4%, respectively.…”

Section: Methodsmentioning

confidence: 99%

Effects of CYP2C19 Genetic Polymorphisms on Atomoxetine Pharmacokinetics

Choi¹,

Bae²,

Lee³

et al. 2014

Self Cite

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.

Reviews in Analytical Chemistry

“…ESI was used as an ion source. The analytes and IS were detected using MRM mode and the m/z was 44 and 256 for the analyte and 116 and 268 for the IS, respectively [141,142]. Further LC-MS/MS methods for the quantification of ATX extracted from human plasma [44,[143][144][145], blood, oral fluids, sweat, urine [146], and hair [147] samples are reported in Table 2.…”

Section: Liquid Chromatography (Lc)mentioning

confidence: 99%

Review on analytical methods for quantification of ADHD drugs in human biological samples

Sundari¹,

Amuthalakshmi²,

Nalini³

2020

Attention deficit hyperactivity disorder (ADHD) is a common neuro-developmental disorder. The symptoms of ADHD include difficulty in attention, memory and impulse control. Many pharmaceutical formulations (stimulants and non-stimulants) are available on the market to treat ADHD symptoms. The most commonly used drugs for treatment are amphetamine, methylphenidate, atomoxetine, bupropion, guanfacine and clonidine. In the field of pharmaceuticals, bioanalysis is an important tool used for the quantification of drugs and their metabolites present in biological samples using various analytical methods. Although a number of analytical methods were reported for the quantification of these drugs in biological samples of experimental animals, due to species differences, it is important to develop analytical methods to quantify these drugs in human biological samples to aid forensic and pharmacokinetic studies. In this review, we compile the bio-analytical methods such as spectrophotometry, spectrofluorimetry, mass spectrometry, electrophoresis, liquid chromatography and gas chromatography used for the quantification of ADHD drugs in human biological samples such as blood, plasma, serum, oral fluids, sweat, hair and urine based on earlier published articles from various journals.