Impact of the CYP2D6 Genotype on the Clinical Effects of Metoprolol: A Prospective Longitudinal Study

Abstract

After administration of metoprolol, plasma concentrations of the drug are markedly higher in CYP2D6 poor metabolizers (PMs) than in non-PMs. In a prospective double-blind 3-month study, we investigated whether this translates into differences in metoprolol's effects after initiation of therapy. Despite administering equal doses to PMs and non-PMs, metoprolol plasma concentrations were 4.9-fold higher in the PM group. Metoprolol evoked significantly and persistently greater reductions in heart rate, diastolic blood pressure, and mean arterial pressure in PMs than in non-PMs. It appears, therefore, that the CYP2D6 genotype contributes to interindividual differences in metoprolol response.

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…Indeed, the emphasis of this review has been on drug efficacy and agent selection. However, there is significant evidence supporting variants predicting adverse events including the hyperuricemia of thiazide use 94 , bradycardia associated with β-blockers [5][6][7][8]95,96 , and ACEI-related cough 97 .…”

“…However, a prospective, double-blind, longitudinal study of metoprolol use found significant differences in diastolic BP (DBP), QT interval, heart rate, and incidence of bradycardia 6,7 . As such, the Dutch pharmacogenomics working group (DPWG) has endorsed CYP2D6 screening with the use of metoprolol 8 .…”

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

“…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.…”

“…Only one other study was conducted in patients with HF as in this study. 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.…”