Genetic Variation in the CYP2D6 Gene Is Associated With a Lower Heart Rate and Blood Pressure in β-Blocker Users

Abstract

Several beta-blockers are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6*4 is the main polymorphism leading to decreased enzyme activity. The clinical significance of impaired elimination of beta-blockers is controversial, and most studies suffer from inclusion of small numbers of poor metabolizers (PMs) of CYP2D6. In this study, the association between CYP2D6*4 and blood pressure or heart rate was examined in 1,533 users of beta-blockers in the Rotterdam Study, a population-based cohort study. In CYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (P < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio = 3.86; 95% confidence interval 1.68-8.86; P = 0.0014). The diastolic blood pressure in PMs was 5.4 mm Hg lower in users of beta-blockers metabolized by CYP2D6 (P = 0.017) and 4.8 mm Hg lower in metoprolol users (P = 0.045) compared with EMs. PMs are at increased risk of bradycardia.

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

“…19 Three of the studies were conducted primarily in individuals with hypertension, 15,20,21 one was in patients treated for acute myocardial infarct, 22 whereas one was a population-based study in which the indication was not mentioned. 23 Concentrations of the active S-enantiomer were measured in two of the studies 15,19 and intergenotype differences in S-metoprolol concentrations were observed, although these were not as marked in extent as in our study.…”

“…In the three studies mentioned above [21][22][23] that showed greater clinical effects in patients with no functional alleles, there was also some evidence of greater effects in patients with a single functional allele. Rau et al 21 stated that although it was not a specific aim of the study, a significant trend for a greater decrease in heart rate and diastolic blood pressure was seen from EMs through IMs to PMs.…”

“…This is consistent with some, 15,19,20,26 but not all of the earlier patient studies. [21][22][23]27 Three studies have now shown a correlation between CYP2D6 genotype and clinical effects of metoprolol. [21][22][23] Rau et al 21 studied patients treated with extended release metoprolol primarily for hypertension and showed greater reductions in heart rate, diastolic blood pressure and mean arterial pressure in patients with no functional alleles (n ¼ 17) versus patients with one or two functional alleles (n ¼ 71).…”

“…[21][22][23] Rau et al 21 studied patients treated with extended release metoprolol primarily for hypertension and showed greater reductions in heart rate, diastolic blood pressure and mean arterial pressure in patients with no functional alleles (n ¼ 17) versus patients with one or two functional alleles (n ¼ 71). 21 These findings are supported by a populationbased study by Bijl et al, 23 who found that individuals with no functional alleles (n ¼ 34) had significantly lower heart rates and diastolic blood pressure compared with the wildtype (*1/*1) genotype (n ¼ 451). A further study in patients with acute myocardial infarct, showed higher mean heart rates in patients with greater CYP2D6 activity.…”

Interaksjoner mellom metoprolol og antidepressive legemidler

“…5-10 % av personer av kaukasisk (vesteuropeisk) avstamning har en homozygot defekt i CYP2D6-funksjonen og er såkalte langsomme omsettere. Disse har en økt risiko for bivirkninger, spesielt bradykardi, ved bruk av anbefalte doser metoprolol (2,3). For den resterende delen av befolkningen -de som har funksjonell CYP2D6-metabolisme -innebaerer bruk av metoprolol sammen med legemidler som hemmer CYP2D6, en risiko for forhøyet plasmakonsentrasjon av metoprolol og økt fare for bivirkninger.…”