Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol‐associated adverse effects

Wuttke, H; Rau, Thomas; Heide, R.; Bergmann, Klaus von; Böhm, Michael; Weil, Joachim; Werner, Dierk; Eschenhagen, Thomas

doi:10.1067/mcp.2002.127111

Cited by 161 publications

(143 citation statements)

References 37 publications

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…substrate drugs [5][6][7]. The most frequent non-functional allelic variant is CYP2D6*4 in Caucasians (European white population) with an allele frequency of 18-23% [8].…”

Section: Introductionmentioning

confidence: 99%

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Kiss

Tóth

Juhasz

et al. 2018

Microchemical Journal

View full text Add to dashboard Cite

Hungary Highlights• CYP2D6 genotype-based phenotype estimation is of particular importance to personalized medication strategy.• The non-sequencing genotyping platform identified the most frequent CYP2D6 allelic variants (in 67% of the donors).• The gain-of-function mutation (-1584C>G) could explain the underestimation of CYP2D6 genotype-based prediction.• Some rare loss-of-function mutations that were not captured, could result in overestimation of CYP2D6 activity prediction.• CYP2D6 phenotype overestimation may also come from external factors modifying CYP2D6 activity or altering hepatic function.• A comprehensive genotyping and consideration of phenoconversion can improve the genotype-based CYP2D6 phenotype prediction. 2 AbstractGenetic polymorphism of cytochrome P450s results in clinically significant modifications in patients' drug metabolizing capacities. CYP2D6 has a crucial role in the elimination of several clinically important drugs (antiarrhythmics, beta-adrenergic blockers, psychopharmacons and analgesics); however, the prediction of the phenotypic appearance of CYP2D6 is a challenge. Since single nucleotide polymorphisms and gene copy number variations (gene deletion and multiplication) frequently occur in CYP2D6 gene, CYP2D6 activity particularly depends on the genetic factors.Microsomal CYP2D6 activities (dextromethorphan O-demethylation) and CYP2D6 genotypes for the most frequent allelic variants (CYP2D6*3, *4, *5, *6, *10, *41 and duplication) were determined in 128 human liver samples derived from Hungarian organ donors. Substantial inter-individual variations were observed in CYP2D6 metabolic activities that were successfully predicted from the CYP2D6 genotypes in 67% of the donors. The underestimation of CYP2D6 phenotypes in 12.5% of the donors was assumed to be originated from the overlapping ranges of CYP2D6 activity among similar diplotypes or from the presence of -1584C>G in the promoter region evoking increased transcription of the wild-type CYP2D6 allele. In an appreciable number of donors (20.3%), the genotype-based CYP2D6 phenotype prediction was overestimated because of the rare CYP2D6 allelic variants which were not included in our genotyping platform or some external factors that could alter CYP2D6 activity (medication with CYP2D6 substrate/inhibitor) and hepatic function (Augmentin therapy, chronic alcohol consumption).In conclusion, CYP2D6 genotyping for the most frequent allelic variants was able to reliably predict CYP2D6 phenotypes in most donors; however, the external factors modifying the phenotypic appearance of CYP2D6 had to be taken into account. Personalized medication strategy should include monitoring of CYP2D6 genotype in a more comprehensive manner 3 and should take external factors into consideration for an appropriate prediction of CYP2D6 metabolizing capacity.

show abstract

“…substrate drugs [5][6][7]. The most frequent non-functional allelic variant is CYP2D6*4 in Caucasians (European white population) with an allele frequency of 18-23% [8].…”

Section: Introductionmentioning

confidence: 99%

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Kiss

Tóth

Juhasz

et al. 2018

Microchemical Journal

View full text Add to dashboard Cite

show abstract

“…The function of the CYP2D6 polymorphisms in drug interaction profiles, side effects and therapeutic outcome is well documented for UMs and PMs. [6][7][8][9][10] Genotyping before treatment has been postulated as a useful tool in preventing side effects and providing dose recommendations. 11,12 However, there are little data on the clinical impact of CYP2D6 polymorphisms on therapeutic drug treatment, response to therapy and side effects of IMs.…”

Section: Introductionmentioning

confidence: 99%

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

et al. 2009

View full text Add to dashboard Cite

The cytochrome P450 2D6 (CYP2D6) isoenzyme metabolizes about 25% of clinically used drugs. The impact of CYP2D6 metabolizer status on therapeutic outcome was assessed in 365 psychiatric in-patients treated with neuroleptics or antidepressants. Length of hospitalization and response onset were prolonged for patients receiving CYP2D6 drugs. Intermediate metabolizers (IMs) receiving CYP2D6 doses above the population median had more side effects after 4 weeks than extensive metabolizers with abovemedian doses (9/13, 69% vs 4/23, 17%, P ¼ 0.003), than IMs with belowmedian doses (5/22, 23%, P ¼ 0.012) and IMs with other medication (24/84, 29%, P ¼ 0.009). The Clinical Global Impression scale response was lower for IMs treated with CYP2D6 drugs (3/42, 7%) than for IMs with other medication (21/84, 25%, P ¼ 0.017) probably due to increased side effects. Identification of IM status (38% of study population) may help to reduce side effects and length/cost of hospitalization. Thus, not only poor and ultrarapid metabolizer but also IMs may benefit from CYP2D6 genotyping. This is of paramount interest since it greatly improves cost/benefit estimations for pretreatment CYP2D6 screening.

show abstract

“…The relationship between CYP2D6 genotype and the occurrence of adverse effects from metoprolol was the subject of study by Wuttke et al [17]. They found a statistically significant approximately 5-fold increased risk of adverse reactions (either b-blocker specific, for example, symptomatic bradycardia, or non-specific, for example nausea) in PMs (p < 0.0001).…”

Section: Resultsmentioning

confidence: 99%

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

Wojtczak

Skrętkowicz

2014

Pharmacological Reports

View full text Add to dashboard Cite

The currently used b-blockers differ in their selectivity for b 1 -and b 2 -adrenergic receptors, lipophilicity and route of elimination. Metoprolol is one of the most commonly used b-blockers in the treatment of ischemic heart disease. Metoprolol is a lipophilic b 1 -selective blocker. This drug is well absorbed from the gastrointestinal tract and undergoes extensive distribution in body tissues; it also passes through the blood-brain barrier. The highest plasma concentration value of metoprolol is reached approximately 2 h after administration of a single dose. Metoprolol is extensively metabolized (oxidation) in the liver by the CYP2D6 isoenzyme of cytochrome P450 [2].The gene encoding the CYP2D6 enzyme is highly polymorphic. The CYP2D6 oxidation polymorphism has a major impact on the Background:Metoprolol is the one of the most commonly used b-blockers in the treatment of ischemic heart disease and it is extensively metabolized in the liver undergoing oxidation by CYP2D6 isoenzyme of cytochrome P450. Gene encoding the CYP2D6 enzyme is characterized by genetic polymorphism. The CYP2D6 oxidation polymorphism has a major impact on the effectiveness and safety of the treatment. The aim of the study was to evaluate the relationship between plasma concentration of metoprolol and the CYP2D6 genotype in patients with ischemic heart disease. Methods: Fifty patients were interviewed and subsequently enrolled into the study. The patients received metoprolol twice daily at a dose of 50 mg. The blood samples were analyzed for two major defective alleles for CYP2D6 -CYP2D6*4 and CYP2D6*3 -by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Metoprolol concentration in plasma was determined by using the new and unique high-performance liquid chromatography (HPLC) method in the author's own modification with Corona CAD detector (Charged Aerosol Detection). Results: In the test group, genotypes conditioning poor oxidation (PM) occurred in 3 patients (6%), while 47 patients (94%) had genotypes coding for extensive metabolism (EM). Patients with PM genotypes had significantly higher plasma concentrations of metoprolol than the patients with EM genotype (mean 92.25 AE SD 36.78 ng/ml vs. mean 168.22 AE SD 5.61 ng/ml, respectively). Established relationships were statistically significant (NIR test, p = 0.0009). Conclusions: This study demonstrated that the CYP2D6 genotype remains a major determinant of the metoprolol plasma concentrations. The pharmacogenetic effect is likely to have consequences on both, the clinical benefit of metoprolol treatment and adverse drug reactions. The use of Corona CAD detector seems to be a very good alternative method for the determination of metoprolol concentration in plasma.

show abstract

Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol‐associated adverse effects

Cited by 161 publications

References 37 publications

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

Contact Info

Product

Resources

About