Disposition and Metabolic Fate of Atomoxetine Hydrochloride: The Role of CYP2D6 in Human Disposition and Metabolism

Sauer, John‐Michael; Ponsler, G. Douglas; Mattiuz, Edward L.; Long, Amanda; Witcher, Jennifer; Thomasson, Holly R.; DeSante, Karl A.

doi:10.1124/dmd.31.1.98

Cited by 140 publications

(149 citation statements)

References 7 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…Atomoxetine is well absorbed in gastrointestinal tract and predominantly metabolized by cytochrome P4502D6 (CYP2D6). After oral administration of 20 mg twice daily in adults, the C max have been observed in the range of 160-180 ng/ml (0.55-0.62 μM) in CYP2D6 extensive metabolizers and up to 925 ng/ml (3.17 μM) in genetically deficient CYP2D6 metabolizers (Sauer et al, 2003). In our in vitro studies, atomoxetine proved to be the most potent P-glycoprotein inhibitor of all the tested agents potentially utilized to treat ADHD.…”

Section: Discussionmentioning

confidence: 78%

Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein

Zhu

Wang

Donovan

et al. 2008

European Journal of Pharmacology

View full text Add to dashboard Cite

The objective of this study was to assess the potential interactions of the drug transporter Pglycoprotein with attention-deficit/hyperactivity disorder (ADHD) therapeutic agents atomoxetine -and the individual isomers of methylphenidate, amphetamine, and modafinil utilizing established in vitro assay. An initial ATPase assay indicated that both d-and l-methylphenidate have weak affinity for P-glycoprotein. The intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123 in the P-glycoprotein overexpressing cell line LLC-PK1/MDR1 was determined to evaluate potential inhibitory effects on P-glycoprotein. The results demonstrated that all compounds, except both modafinil isomers, significantly increased doxorubicin and rhodamine123 accumulation in LLC-PK1/MDR1 cells at higher concentrations. To investigate the P-glycoprotein substrate properties, the intracellular concentrations of the tested compounds in LLC-PK1/MDR1 and P-glycoprotein negative LLC-PK1 cells were measured in the presence and absence of the Pglycoprotein inhibitor PSC833. The results indicate that the accumulation of d-methylphenidate in LLC-PK1 cells was 32.0% higher than in LLC-PK1/MDR1 cells. Additionally, coadministration of PSC833 leads to 52.9% and 45.6% increases in d-modafinil and l-modafinil accumulation, respectively, in LLC-PK1/MDR1 cells. Further studies demonstrated that l-modafinil transport across LLC-PK1/MDR1 cell monolayers in the basolateral-to-apical (B-A) direction was significantly higher than in the apical-to-basolateral (A-B) direction. PSC833 treatment significantly decreased the transport of l-modafinil in B-A direction. In conclusion, our results suggest that all tested agents with the exception of modafinil isomers are relatively weak P-glycoprotein inhibitors. Furthermore, P-glycoprotein may play a minor role in the transport of d-methylphenidate, dmodafinil, and l-modafinil.

show abstract

Section: Discussionmentioning

confidence: 78%

Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein

Zhu

Wang

Donovan

et al. 2008

European Journal of Pharmacology

View full text Add to dashboard Cite

show abstract

“…Atomoxetine, a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder in children and adults (Newcorn et al, 2005). In humans, atomoxetine undergoes extensive metabolism of 4-hydroxylation by CYP2D6 to form 4-hydroxyatomoxetine and is also transformed into a minor metabolite, N-demethylatomoxetine, mainly by CYP2C19 (Ring et al, 2002;Sauer et al, 2003). The enzyme kinetics of CYP2D6.1, CYP2D6.10, and CYP2D6.17 variants toward atomoxetine 4-hydroxylation were characterized, and the results indicated that CYP2D6.10 and CYP2D6.17 exhibited enzyme efficiency (as CL int ), which was 8.58 and 21.9% of CYP2D6.1.…”

Section: Resultsmentioning

confidence: 99%

Comparative Metabolic Capabilities and Inhibitory Profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17

Shen

He²,

Liu³

et al. 2007

Drug Metab Dispos

152

129

View full text Add to dashboard Cite

ABSTRACT:Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNAexpressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences.

show abstract

“…Another example that showed a similar pattern was atomoxetine, which is metabolized by CYP2D6 (aromatic 4-hydroxylation, major pathway in CYP2D6 EM) and CYP2C19 (N-demethylation) (Sauer et al, 2005). In CYP2D6 EM subjects, 4-OH atomoxetine glucuronide constitutes the major circulating moiety, while the plasma AUC ratios of N-desmethyl atomoxetine and 4-hydroxyatomoxetine to parent were low (,0.1) (Sauer et al, 2003). Moreover, in CYP2D6 PM, the AUC ratio of N-desmethyl atomoxetine to parent drug was 0.33 to 0.42 (Sauer et al, 2003;FDA Clinical Pharmacology Review: http:// www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-411_Strattera_ biopharmr_P2.pdf), thus constituting a moiety that needs to be considered for assessment for potential DDI under the current EMA and draft FDA Guidance.…”

Section: Special Considerations Genetic Polymorphismsmentioning

confidence: 99%

“…In CYP2D6 EM subjects, 4-OH atomoxetine glucuronide constitutes the major circulating moiety, while the plasma AUC ratios of N-desmethyl atomoxetine and 4-hydroxyatomoxetine to parent were low (,0.1) (Sauer et al, 2003). Moreover, in CYP2D6 PM, the AUC ratio of N-desmethyl atomoxetine to parent drug was 0.33 to 0.42 (Sauer et al, 2003;FDA Clinical Pharmacology Review: http:// www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-411_Strattera_ biopharmr_P2.pdf), thus constituting a moiety that needs to be considered for assessment for potential DDI under the current EMA and draft FDA Guidance. These examples highlight the need to evaluate the abundance of circulating metabolites in relation to the genotype and phenotype of the metabolizing enzymes, if genetic polymorphisms are known to exist for the particular enzyme of interest.…”

Section: Special Considerations Genetic Polymorphismsmentioning

confidence: 99%

Which Metabolites Circulate?

2013

View full text Add to dashboard Cite

Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (f m ). Our analysis suggests that f m is the major determinant of total drug M/P ratio for amine, alcohol, N-and S-oxide, and carboxylic acid metabolites. Passage from the hepatocyte to systemic circulation does not appear to be limiting owing to the vast majority of metabolites formed being relatively lipid permeable. In some cases, active transport plays an important role in this process (e.g., carboxylic acid metabolites). Differences in total parent drug clearance and metabolite clearance are attenuated by the reduction in lipophilicity introduced by the metabolic step and resultant compensatory changes in unbound clearance and protein binding. A small subclass of these drugs (e.g., terfenadine) is unintentional prodrugs with very high parent drug clearance, resulting in very high M/P ratios. In contrast, arenol metabolites show a more complex relationship with f m due largely to the new metabolic routes (conjugation) available to the metabolite compared with the parent drug molecule. For these metabolites, a more thorough understanding of the elimination clearance of the metabolite is critical to discern the likelihood of whether the phenol will constitute a major circulating metabolite.

show abstract

Disposition and Metabolic Fate of Atomoxetine Hydrochloride: The Role of CYP2D6 in Human Disposition and Metabolism

Cited by 140 publications

References 7 publications

Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein

Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein

Comparative Metabolic Capabilities and Inhibitory Profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17

Which Metabolites Circulate?

Contact Info

Product

Resources

About