Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol (original) (raw)
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Saudi Journal of Biological Sciences, 2020
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Population Pharmacokinetic Analysis of Bisoprolol in Patients with Stable Coronary Artery Disease
European journal of drug metabolism and pharmacokinetics, 2017
Bisoprolol is a selective beta adrenergic antagonist commonly used in treatment of coronary artery disease (CAD). The aim of our analysis was to estimate and identify different factors that could affect bisoprolol clearance (CL) and develop a population pharmacokinetic model in patients with stable coronary artery disease (CAD). Population pharmacokinetic analysis was performed by using sixty-six plasma concentrations from the same number of patients (mean age 60.26 ± 9.68 years; mean total body weight 80.37 ± 12.93 kg) with CAD. We examined the effects of various clinical and demographic parameters using nonlinear mixed-effect modeling (NONMEM) with ADVAN1 with TRANS2 subroutine. The pharmacokinetics of bisoprolol in patients with CAD were suitably defined by an oral one-compartment model. The typical mean value for bisoprolol CL, estimated by the base model, in the target population was 6.76 l/h. The only demographic covariate which affected bisoprolol pharmacokinetic variability ...
British Journal of Clinical Pharmacology, 2020
Aims: CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain. Methods: We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta-analyses were performed on the impact of CYP2D6-inferred phenotypes on heart rate reduction (HR), diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all-type adverse events (AE) and bradycardia. Results: Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta-analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (p=0.017), and of SBP and DBP by 3 mmHg (p=0.0048) for PM compared to non-PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4-fold for PM, although significant heterogeneity was observed in regards to bradycardia, which limits the scope of this finding. Conclusions: Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR, and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6-inferred phenotypes. What is already known about this subject • CYP2D6 highly contributes to drug metabolism. It contains also contains several genetic polymorphisms affecting its enzymatic activity. • Metoprolol pharmacokinetics are significantly affected between genotype-inferred phenotypes of CYP2D6, but the impacts on the clinical response of patients to patients have not been summarized. What this study adds • This paper reviews the cumulative results of the effects of CYP2D6 genetic polymorphisms for patients on metoprolol treatment. • Patients possessing an inactive CYP2D6 phenotype have increased clinical effects and bradycardia with metoprolol, compared to those with an active CYP2D6 metabolic capacity. • More prospective data should be generated to suggest the implementation of a personalized approach to CYP2D6-mediated β-blocker therapy.
International Journal of Sciences: Basic and Applied Research, 2017
Left ventricular hypertrophy (LVH) is commonly present in patients with hypertension (HT). Angiotensin-II and chronic stimulation of β1-adrenergic receptors (β1-AR) contribute to LVH progression in hypertensive patients. Angiotensin-II Receptor Blocker (ARB) has been shown effectively regression left ventricular mass index. The aim of this study was to identify the efficacy of Bisoprolol reducing left ventricular hypertrophy (LVH) in Arg389Arg hypertensive patients receiving ARB. This prospective pre-post test cohort study included 39 male hypertensive patients who met the inclusion criteria. Patients underwent 24-hour Ambulatory Blood Pressure Monitoring (ABPM) procedures, echocardiographic examination to assess LVH pre-post 6 months of ARB treatment. Regimen was optimized based on office blood pressure. Arg389Gly β1-AR polymorphism was examined using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method and confirmed by sequenzing method.
Clinical Pharmacology & Therapeutics, 2008
several β-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 β-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 β-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 β-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.
The Pharmacogenomics Journal, 2009
The aims of this study were to examine the relationships between CYP2D6 genotype and metoprolol dose, S-and R-metoprolol concentrations and clinical effects in patients with systolic heart failure. Data were obtained for 52 subjects, of which 27 had 2 functional alleles (24/27, CYP2D6*1/*1), 22 had 1 functional allele (18/22, CYP2D6*1/*4) and 3 had no functional alleles (CYP2D6*4/*4). Median dose-adjusted concentrations of S-metoprolol (active) were 6.3-and 3.2-fold higher in subjects with zero or one functional allele (P ¼ 0.016 and P ¼ 0.006), respectively, compared with subjects with two functional alleles. For the R-enantiomer (inactive), these concentrations were 10.7-and 3.7-fold higher (P ¼ 0.013 and P ¼ 0.003), respectively. Despite clear gene-concentration differences, no relationships between CYP2D6 genotype and dose or clinical effects could be shown. Although the number with no functional alleles was too small (n ¼ 3) to show effects, in patients with 1 functional allele other sources of variance are likely to be obscuring differences in clinical effects.
Influence of phenotype and pharmacokinetics on β-blocker drug target pharmacogenetics
The Pharmacogenomics Journal, 2006
Two common polymorphisms in the b 1-adrenergic receptor gene, Ser49Gly and Arg389Gly, are associated with variable antihypertensive response to metoprolol. We sought to determine whether similar pharmacogenetic associations were present with the negative chronotropic response phenotype to metoprolol. Metoprolol was titrated in 54 untreated hypertensive patients to achieve blood pressure control. We found no association between either resting or exercise heart rate at baseline (untreated) or in response to metoprolol by codon 389 genotype. In contrast, when compared by codon 49 genotype, Ser49 homozygotes had significantly higher resting heart rates at baseline (untreated) than Gly49 carriers (82710 versus 74711 bpm, respectively, P ¼ 0.016). When corrected for plasma concentration, we found no difference in reduction in exercise heart rate in response to metoprolol between Ser49 homozygotes and Gly49 carriers (0.7570.11 versus 0.5770.17%/ng/ml, respectively, P ¼ 0.37). However, if one fails to account for plasma concentration, trends toward a significant difference in heart rate reduction are seen between Ser49 homozygotes and Gly49 carriers (31% reduction versus 25% reduction, P ¼ 0.05). Our data suggest that neither the b 1-adrenergic receptor Arg389Gly, nor the Ser49Gly polymorphisms are associated with variable negative chronotropic response to metoprolol. In addition, our data highlight the importance of measuring metoprolol concentration in order to account for variable pharmacokinetics and avoid misinterpretation of the data.