Influence of CYP2D6 Genotype on Metoprolol Plasma Concentration and β-Adrenergic Inhibition During Long-Term Treatment

Nozawa, Takashi; Taguchi, Masato; Tahara, Katsutoshi; Hashimoto, Yoshiaki; Igarashi, Norio; Nonomura, Makoto; Kato, Bunichi; Igawa, Akihiko; Inoue, Hiroshi

doi:10.1097/01.fjc.0000184117.76188.68

Cited by 57 publications

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“…The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with the CYP2D6*1/*1 or *1/*2 genotype [12]. Nozawa et al showed, that in patients routinely treated with metoprolol, the CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol [13].…”

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

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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.

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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

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“…14) In addition, isoproterenol-induced percentage increases in heart rate in Japanese patients with CYP2D6*10/*10, who were routinely treated with metoprolol, were less than those in the patients with CYP2D6*1/*1 or *1/*2. 34) These findings suggested that a lower dose of metoprolol may be used in the patients with CYP2D6*10. 14,34) In conjunction with the previous study, the present findings suggested that the pharmacokinetic variability of S-carvedilol is smaller than that of metoprolol (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…34) These findings suggested that a lower dose of metoprolol may be used in the patients with CYP2D6*10. 14,34) In conjunction with the previous study, the present findings suggested that the pharmacokinetic variability of S-carvedilol is smaller than that of metoprolol (Fig. 4).…”

Section: Discussionmentioning

confidence: 98%

Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

Honda

Ogura

Toyoda

et al. 2006

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist used clinically to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1-4) Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low bblocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)In the previous study, we investigated the effect of genetic polymorphisms of cytochrome P450 (CYP) 2D6 on the pharmacokinetics of R-and S-carvedilol in 23 healthy Japanese volunteers.8) The large interindividual variability was observed in the pharmacokinetics of carvedilol, and the coefficient of variation of the weight (WT)-corrected oral clearance ((CL/F)/ WT) value among the subjects was 36.1%. In addition, the (CL/F)/WT value was highly correlated with the apparent distribution volume ((V/F)/WT) value among the subjects, suggesting that the interindividual difference in bioavailability (F) was at least partly responsible for the pharmacokinetic variability of carvedilol. The (CL/F)/WT and (V/F)/WT values of R-and S-carvedilol were significantly lower in healthy volunteers with at least one CYP2D6*10 allele than those with the CYP2D6*1/*1 and *1/*2 genotype. The result suggested that the systemic and/or pre-systemic metabolism of R-and S-carvedilol in the liver is significantly decreased in Japanese subjects with the CYP2D6*10 allele.Carvedilol is metabolized extensively via aliphatic sidechain oxidation and conjugation pathways, as well as the aromatic ring oxidation pathway which is mediated mainly by CYP2D6. 6) Oldham et al. reported that considerable metabolic activity for carvedilol is observed in CYP1A2, 2C9, 2D6, and 3A4. 9) On the other hand, it is still unclear whether the other P450s are involved in the metabolism of carvedilol. However, a substrate of CYP2C9, such as phenytoin, is partly catalyzed by another CYP2C subfamily, CYP2C19. 10)CYP3A5 is another important CYP3A protein in the liver, the substrate specificity of which largely overlaps with that of CYP3A4.11) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 1A1, 2B4, and 2B7 as well as human hepatic microsomes are capable of catalyzing the glucuronidation of carvedilol.12) Moreover, carvedilol has high affinity for the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Giessmann et al. reported that the intestinal expression of P-gp is a major variable in the disposition of carvedilol. 13)In the presen...

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“…Есть данные, что бисопролол в отличие от метопролола оказывает относительно постоянный бета-блокирую-щий эффект вне зависимости от генотипа CYP2D6 [53], и в связи с этим может быть более предпочтителен у по-жилых, чем метопролол [13]. Кроме того, преимуществом бисопролола перед всеми другими β-адреноблокаторами является его двойной путь выведения, в связи с чем кор-рекция дозы требуется только при тяжелой степени по-чечной или печеночной недостаточности.…”

Section: Antiarrhythmic Drugs In Elderly Patients антиаритмические срunclassified

Antiarrhythmic drugs use in elderly patients. Vaughan Williams class I and II drugs

Ушкалова

Zyryanov

Затолочина

et al. 2016

Racionalʹnaâ farmakoterapiâ v kardiologii

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Старение ассоциируется со множественными изме-нениями в структуре, электрофизиологических свой-ствах и функциях миокарда, уменьшением его ответа на катехоламины и угнетением барорецепторных рефлек-сов [1]. Эти изменения предрасполагают к развитию сер-дечных аритмий, являющихся важной причиной забо-леваемости и смертности в пожилом возрасте [1][2][3].В свою очередь сердечные аритмии повышают риск развития сердечной недостаточности и инсульта, яв-ляются основной причиной внезапной смерти, а также множественных симптомов (сердцебиения, боль в гру-ди, одышка, синкопе и др.), снижающих качество жиз-ни пожилых больных и приводящих к развитию трево-ги и депрессии [4,5]. Кроме того, аритмии могут клини-чески проявляться спутанностью сознания и необъясни-мыми падениями, которые у лиц пожилого возраста со-пряжены с повышенным риском переломов [6].Распространенность аритмий увеличивается с воз-растом. При целенаправленном скрининге желудочковые аритмии обнаруживаются у 70-80% пациентов старше 60 лет, хотя во многих случаях остаются бессимптомны-ми [7][8], фибрилляция предсердий -менее чем у 1% лиц моложе 60 лет и у 9-17,6 % -старше 80 лет [9][10][11]. Бо-лее 80% внезапных сердечных смертей возникает у лиц старше 65 лет [12].Данные об эффективности и безопасности анти-аритмической терапии у пациентов очень пожилого возраста ограничены, так как в рандомизированных контролируемых исследованиях (РКИ) участвовало край-не небольшое число пациентов старше 80 лет [8]. Оцен-ку эффективности антиаритмической терапии у этой ка-тегории пациентов затрудняет и лимитированная ожи-даемая продолжительность жизни.Помимо возрастных изменений сердечно-сосуди-стой системы при проведении фармакотерапии у паци-ентов старшего возраста следует учитывать их субъективное восприятие аритмии, отличное от такового у более мо-лодых, и обусловленное нарушением множественных фи-зических и когнитивных функций, а также взаимодей- Применение антиаритмических препаратов I класса у пожилых пациентов ограничивают их нежелательные реакции, аритмогенное действие (I A и I C) и высокий риск лекарственных взаимодействий. Применения дизопирамида следует избегать из-за выраженных антихолинергических свойств, сопряженных с риском развития ког-нитивных и соматических расстройств и падений у самых пожилых пациентов. Имеющиеся данные позволяют предположить, что у пожилых лиц нет существенных ограничений к применению β-адреноблокаторов. Однако для определения препаратов данной группы с оптимальным соотношением польза/риск у лиц пожилого воз-раста с коморбидностью необходимы дальнейшие исследования. Use of class I antiarrhythmic drugs in the elderly is limited by their adverse drug reactions (ADRs), proarrhythmic effect (I A и I C) and high risk of drug interactions. Disopyramide use should be avoided due to its strong anticholinergic properties associated with the risk of cognitive and physical disorders and falls in the "very elderly" patients. Available data suggest that elderly patients do not have significant limitations for beta-blockers use. However to determine beta...

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Influence of CYP2D6 Genotype on Metoprolol Plasma Concentration and β-Adrenergic Inhibition During Long-Term Treatment

Cited by 57 publications

References 22 publications

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

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

Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

Antiarrhythmic drugs use in elderly patients. Vaughan Williams class I and II drugs

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