CYP2D6 genotype affects age-related decline in flecainide clearance

Doki, Kosuke; Homma, Masato; Kuga, Keisuke; Aonuma, Kazutaka; Kohda, Yukinao

doi:10.1097/fpc.0b013e3283588fe5

Cited by 15 publications

(12 citation statements)

References 23 publications

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“…Although the metabolic function of CYP2D6 is reported not to decline by aging, other CYPs such as CYP1A2, CYP2C9, CYP2C19, and CYP3A4 do . This is important in 2 aspects.…”

Section: Discussionmentioning

confidence: 99%

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Discontinuation and dose adjustment of metoprolol after metoprolol‐paroxetine/fluoxetine co‐prescription in Dutch elderly

Bahar

Wang

Bos

et al. 2018

Pharmacoepidemiology and Drug

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PurposeCo‐prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug‐drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly.MethodsWe performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co‐prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co‐prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).ResultsCombinations of metoprolol‐paroxetine/fluoxetine, metoprolol‐citalopram, and metoprolol‐mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol‐citalopram, metoprolol‐paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77‐1.48; OR = 0.87, 95% CI:0.57‐1.33, respectively). In comparison with metoprolol‐mirtazapine, metoprolol‐paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01‐2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03‐2.53).ConclusionParoxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

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“…Although the metabolic function of CYP2D6 is reported not to decline by aging, other CYPs such as CYP1A2, CYP2C9, CYP2C19, and CYP3A4 do . This is important in 2 aspects.…”

Section: Discussionmentioning

confidence: 99%

“…Although the metabolic function of CYP2D6 is reported not to decline by aging, other CYPs such as CYP1A2, CYP2C9, CYP2C19, and CYP3A4 do. [36][37][38] This is important in 2 aspects. Firstly, metoprolol is mainly metabolized by CYP2D6 and secondarily metabolized by CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

Discontinuation and dose adjustment of metoprolol after metoprolol‐paroxetine/fluoxetine co‐prescription in Dutch elderly

Bahar

Wang

Bos

et al. 2018

Pharmacoepidemiology and Drug

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“…Another Asian-specific genetic factor affecting flecainide efficacy is CYP2D6*10, a polymorphism in the gene encoding the main metabolic enzyme for flecainide. Since about 60% of Japanese patients were reported to be CYP2D6*10 carriers [29], this variant as well as the SCN5A promoter HapB may result in a lower flecainide dose requirement in this population [30,31].…”

Section: Discussionmentioning

confidence: 99%

SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients

Doki¹,

Homma²,

Kuga

et al. 2013

Pharmacogenetics and Genomics

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“…Age CYP2D6 seems to be functional already in first 2 weeks after birth [85][86][87] and seems generally not to decline substantially with older age; however, definite information is relatively sparse [88,89]. The article by Doki et al [89] found an interesting dependence of the age-related decline in flecainide clearance from the CYP2D6 genotype.…”

Section: Pregnancymentioning

confidence: 96%

“…The article by Doki et al [89] found an interesting dependence of the age-related decline in flecainide clearance from the CYP2D6 genotype. The age-related decline was 28.9% in IMs/PMs but only 6.1% in homozygote EMs.…”

Section: Pregnancymentioning

confidence: 96%

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Haertter

2013

Drug Metabolism and Drug Interactions

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The cytochrome P450 2D6 (CYP2D6) belongs to a group of CYPs considered of utmost importance in the metabolism of xenobiotics. Despite being of only minor abundance in the liver, it is involved in the clearance of >25% of marketed drugs. Accordingly, CYP2D6 can be very efficiently inhibited by a couple of commonly used drugs such as some antidepressants, although induction by any drug has not been observed thus far. CYP2D6 was also one of the first enzymes for which a highly polymorphic expression could be shown leading to a widespread range of functionality, from a complete lack of a functional enzyme to overexpression due to multiplication of active alleles. A clear relationship between the CYP2D6 genotype and adverse events during treatment with CNS-active drugs such as codeine, antidepressants, or antipsychotics could be demonstrated. More recently, some new aspects emerged about the potential endogenous function of CYP2D6 in terms of behavior and brain disorders.

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CYP2D6 genotype affects age-related decline in flecainide clearance

Abstract: This study suggests that CYP2D6 genotype is a determinant factor of age-related decline in flecainide clearance.

Cited by 15 publications

References 23 publications

Discontinuation and dose adjustment of metoprolol after metoprolol‐paroxetine/fluoxetine co‐prescription in Dutch elderly

Discontinuation and dose adjustment of metoprolol after metoprolol‐paroxetine/fluoxetine co‐prescription in Dutch elderly

SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

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