Identification of the Human Cytochromes P450 Responsible for Atomoxetine Metabolism

Ring, Barbara J.; Gillespie, Jennifer S.; Eckstein, James A.; Wrighton, Steven

doi:10.1124/dmd.30.3.319

Cited by 171 publications

(198 citation statements)

References 7 publications

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“…As described by some authors, CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5 involved in the biotransformation of R-and S-fluoxetine to their N-desmethyl metabolites [65,66]. It was also demonstrated that CYP2C9 catalyzes R-fluoxetine demethylation and the formation of S-norfluoxetine is highly dependent on CYP2D6 [65,67].…”

Section: Fluoxetinementioning

confidence: 99%

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Serotonin Toxicity and Cytochrome p450 Poor Metaboliser Genotype Patient Case

Piatkov¹

2017

JIG

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Serotonin toxicity commonly occurs in the context of serotonergic drug overdose or from interactions between multiple serotonergic agents. We describe a 29 year old woman with depression and anxiety who was commenced on regular fluoxetine 20mg/day for 7 weeks, followed by 40 mg/day for 3 weeks. During the 10-week period she began to have increasing agitation and episodes of flushing, sweating and tremor. She presented to the emergency department with a similar acute episode. Following cessation of fluoxetine and treatment with cyproheptadine and diazepam, her symptoms improved and she was discharged the following day. Informed consent was obtained from the patient for genetic testing of her CYP enzymes. Restriction Fragment Length Polymorphism assay (PCR-RFLP) revealed a presence of homozygote rs3892097 and rs1065852 polymorphisms in CYP2D6 and heterozygote 2C19 rs4244285/rs4986893 polymorphisms, which are associated with poor metaboliser phenotype and presence of one copy of CYP1A2 rs35694136 and rs762551. This patient genotype is a very rare case of combined loss-of-function of CYP2D6 and CYP2C19 isozymes. In addition, heterozygote polymorphisms, which are associated with impaired activity of CYP1A2, possibly contribute to low activity of the cytochrome P450 drug metabolising pathway. The involved cytochrome P450 isoforms exhibit genetic polymorphisms that affect their catalytic activity. Keywords: Graphical AbstractSerotonin toxicity developed by patient with loss-of function Cytochrome P450 genetic polymorphisms' combination is described. Genotyping revealed CYP2D6, CYP2C19 and CYP1A2 non-functional polymorphisms previously associated with poor metaboliser phenotype.

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Section: Fluoxetinementioning

confidence: 99%

“…It was also demonstrated that CYP2C9 catalyzes R-fluoxetine demethylation and the formation of S-norfluoxetine is highly dependent on CYP2D6 [65,67]. Their catalytic activities depend on genetic polymorphisms.…”

Section: Fluoxetinementioning

confidence: 99%

Serotonin Toxicity and Cytochrome p450 Poor Metaboliser Genotype Patient Case

Piatkov¹

2017

JIG

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“…A recent meta-analysis reported the number-needed-to-treat (NNT) for atomoxetine treatment response (reduction of Ն25% in ADHD-RS total score from baseline) was 3.43 (95% CI, 2.79-4.45). 18 Signifi cant improvement compared with those treated with placebo has been demonstrated across efficacy measures, in younger (6-7 years) and older (8)(9)(10)(11)(12) However, overall in the treatment of pediatric ADHD, superior effect sizes are consistently observed with immediate-release and long-acting stimulants, as compared to non-stimulants, including atomoxetine. 20 …”

Section: Atomoxetine For Adhd In Children and Adolescentsmentioning

confidence: 99%

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: a review

Hammerness¹,

McCarthy²,

Mancuso³

et al. 2009

NDT

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Objective: This review examines and summarizes the pharmacodynamic and pharmacokinetic properties, short-and longer-term effi cacy, the moderating effect of comorbid disorders, as well as short-and long-term safety and tolerability of atomoxetine for the treatment of pediatric attention-defi cit/hyperactivity disorder (ADHD). Methods: A systematic literature search was performed to review the extant literature on articles pertaining to the pharmacological treatment with atomoxetine in pediatric and/or adolescent ADHD. Results: There is an extensive literature on atomoxetine; over 4000 children have participated in clinical trials of atomoxetine, demonstrating its short-and longer-term effi cacy. In addition, studies have examined the moderating effect of comorbid disorders on atomoxetine response, as well as atomoxetine's therapeutic potential for other psychiatric conditions. Short-and longerterm safety and tolerability continue to be reported. Conclusions: Atomoxetine is indicated for both acute and maintenance/extended treatment of pediatric ADHD. Clinicians and families must be familiar with atomoxetine's evidence base, including its profi le of clinical response and its possible effectiveness in the presence of comorbidity.

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“…13,14) However, it is unclear whether CYP3A4 and CYP3A5 share the metabolic pathway of tadalafil because no systematic study on the CYP3A isoforms involved in the demethylenation of the drug has been reported in the literature to date.…”

Section: )mentioning

confidence: 99%

Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

Takahiro

Nakamura

Kohno

et al. 2015

Biological ^|^ Pharmaceutical Bulletin

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The aim of this study was to characterize the kinetics of metabolite formation of the phosphodiesterase type-5 (PDE5) inhibitors sildenafil and tadalafil by CYP3A4, CYP3A5, and CYP3A7 isoforms. The formations of N-desmethyl sildenafil and desmethylene tadalafil were examined using CYP3A supersomes co-expressing human P450 oxidoreductase and cytochrome b 5 . Both sildenafil N-demethylation and tadalafil demethylenation were catalyzed by CYP3A4, CYP3A5, and to a lesser extent by CYP3A7. The kinetics of desalkyl metabolite formation of the two drugs were well fitted to the Hill equation; however, the Hill coefficients (n) suggested CYP3A-mediated negative cooperativity. Next, we analyzed the kinetics with a two binding sites model assuming two reaction steps: reaction 1 with high-affinity and low-capacity metabolism and reaction 2 with low-affinity and high-capacity metabolism. The kinetics of desalkyl metabolite formation were also fitted to the two binding sites model 1) PDE5 inhibitors have been shown to be an effective vasodilator, and have been used widely as a treatment not only for erectile dysfunction, but also for pulmonary arterial hypertension (PAH).2) Sildenafil and tadalafil are orally active inhibitors of PDE5 that are approved for the treatment of PAH in Japan, but their half-life period in the body differs substantially.3,4) That is, sildenafil has a fairly short half-life of about 4-5 h, whereas tadalafil has a long half-life of about 17.5 h in healthy subjects.5,6) The short half-life of sildenafil makes it the drug of choice in patients with more severe cardiovascular disease, allowing early use of supportive treatment if an adverse clinical event occurs. 7) In contrast, tadalafil has the advantage of once a day dosing compared to sildenafil's three times a day dosing, with implications for patient convenience and compliance. 6,8) Therefore, a transition from sildenafil to tadalafil has been frequently tried in stable patients with PAH. 3,8) In humans, sildenafil is eliminated predominantly by hepatic metabolism and is converted to an active metabolite, N-desmethyl sildenafil, with properties similar to the parent drug.9) The N-demethylation by CYP3A is the major route of metabolism of sildenafil in humans 10) (Fig. 1). Recently, Ku et al. 11) showed that both CYP3A4 and CYP3A5 played a significant role in the metabolism of sildenafil using CYP3A supersomes. That is, the intrinsic clearance for N-dealkylation of sildenafil by CYP3A5 and CYP3A4 were 0.09 and 0.07 µL/ min/pmol P450, respectively. 11) They also demonstrated that the mean rate for N-desalkyl metabolite formation from sildenafil was high in human liver microsome preparations with CYP3A5 activity (heterozygous for CYP3A5*1/*3 alleles) compared to those with null CYP3A5 activity (homozygous for CYP3A5*3 allele).11) These results suggested that genetic polymorphism of CYP3A5 at least partly contributes to interindividual variability in the disposition of sildenafil. On the other hand, tadalafil is eliminated predominantly by oxidative me...

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Identification of the Human Cytochromes P450 Responsible for Atomoxetine Metabolism

Cited by 171 publications

References 7 publications

Serotonin Toxicity and Cytochrome p450 Poor Metaboliser Genotype Patient Case

Serotonin Toxicity and Cytochrome p450 Poor Metaboliser Genotype Patient Case

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: a review

Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

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