Associations between <i>ADRB1</i> and <i>CYP2D6</i> gene polymorphisms and the response to β-blocker therapy in hypertension

Wu, Dingchang; Li, Ganyang; Deng, Maoqing; Song, Wei; Huang, Xiaohua; Guo, Xianzhong; Wu, Ze; Wu, Shiyang; Xu, Jianbing

doi:10.1177/0300060514563151

Cited by 29 publications

(20 citation statements)

References 39 publications

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“…44 Results have shown that homozygote mutant genotype ADRB1 1165G>C is associated with the increase in effectiveness of Metoprolol in treating hypertension, that suggest the selection of anti-hypertension according to genotype of patients. 45 Furthermore, in Korean patients suffering from heart failure, it was observed that people with ADRB1 Gly389X genotype, have shown a better response to Bisoprolol compared to Arg389Arg genotype. These results show that treatment with beta- blocker goes to treatment of each person separately, on the basis of genotype.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Parameters and Over-Responsiveness of Iranian Population to Propranolol

Salehifar¹,

Ebrahim²,

Shiran³

et al. 2017

Adv Pharm Bull

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Purpose: Propranolol is the most widely used treatment for cardiovascular diseases. Dosage range in our patients is usually less than the amount mentioned in references. The aim of the present study was to clarify whether pharmacokinetic differences are able to justify the need for the fewer doses in our patients or not.Methods: Twenty healthy volunteers (10 male) at heart center of Mazandaran University of Medical Sciences were studied. Samples of blood were collected before a single oral dose (40 mg) of Propranolol. Blood samples were taken up to 9 hours after dose. Total plasma concentration of Propranolol was measured by HPLC. Population Pharmacokinetic analysis was performed using population pharmacokinetics modeling software P-Pharm.Results: The mean value for oral plasma clearance (CL/F) was 126.59 ml/hr. The corresponding values for apparent volume of distribution (V/F), t1/2 beta, maximum blood concentration (C max), and time to reach the maximum blood concentration (T max) were 334.12 Lit, 1.98 hr, 40.25 ng/ml, and 1.68 hr, respectively. The observed mean values of V/F of propranolol in the present study were comparable with those reported in the literature. However, the mean values of CL/F of propranolol in current study was significantly higher than those reported in other population (P-value<0.001).Conclusion: This study has confirmed that the pharmacokinetic differences are not able to justify over-responsiveness of Iranian population to propranolol. Pharmacodynamic differences in responding to beta blocker drugs by Renin secretion or having a different sensibility to beta receptors might play a role in making our population have a different response to propranolol.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Parameters and Over-Responsiveness of Iranian Population to Propranolol

Salehifar¹,

Ebrahim²,

Shiran³

et al. 2017

Adv Pharm Bull

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“…Although several studies have found a significant association between CYP2D6 genetic polymorphisms and beta-blocker dose or patient response to metoprolol or carvedilol (6,10–12,32–40), an almost equal number of studies have reported null findings (9,11,13,33,41–45). Our findings regarding carvedilol dose are consistent with the reported findings of Baudhuin et al (32).…”

Section: Discussionmentioning

confidence: 99%

“…Much of the reported research on the effects of CYP2D6 genetic polymorphisms on beta-blockers was from data collected in late-phase (efficacy) clinical trials (6,9–13) or highly controlled early-phase (pharmacokinetics) clinical studies (5,14–17). The reported findings from those studies, therefore, may not be generalizable to patients under routine clinical care.…”

Section: Introductionmentioning

confidence: 99%

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

Luzum

Sweet

Binkley³

et al. 2017

Pharm Res

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Purpose This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. Methods Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n=65) or metoprolol (n=33). Results CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02–0.75] p=0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84–10.30] p=0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (50mg/day). Conclusion Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

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“…Although its efficacy is extremely variable among patients, the presence of CYP2D6 and Adrb1 polymorphisms only provide a partial explanation for this variability (10–12). A previous study investigating Adrb1 promoter methylation suggested that the level of Adrb1 promoter methylation influences the efficacy of Met via the regulation of β1-AR expression (14).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies investigating Adrb1 polymorphisms have focused primarily on the Ser49Gly and Arg389Gly polymorphisms. For instance, Wu et al (12) demonstrated that Chinese patients with essential hypertension that were homozygous for a mutant Adrb1 genotype (Arg389), exhibited an increased sensitivity to Met treatment. By contrast, an additional study demonstrated that subjects with the same CYP2D6 and Adrb1 genotypes exhibited varying responses to Met, which suggests that additional mechanisms responsible for the inter-individual differences in Met responses may exist (13).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the β1 adrenergic receptor in the myocardium results in insensitivity to metoprolol and reduces blood pressure in spontaneously hypertensive rats

Huang

Liu

Wen

et al. 2016

Molecular Medicine Reports

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The β1-adrenergic receptor (AR) is the primary β-AR subtype in the heart and is the target of metoprolol (Met), which is commonly used to treat angina and hypertension. Previous studies have revealed a positive correlation between the methylation levels of the adrenoreceptor β1 gene (Adrb1) promoter in the myocardium with the antihypertensive activity of Met in spontaneously hypertensive rats (SHR), which affects β1-AR expression in H9C2 cells. The aim of the present study was to investigate the effects of myocardial β1-AR downregulation using short-hairpin RNA (shRNA) against Adrb1 on the antihypertensive activity of Met in SHR. Recombinant adeno-associated virus type 9 (rAAV9) vectors carrying Adrb1 shRNA (rAAV9-Adrb1) or a negative control sequence (rAAV9-NC) were generated and used to infect rat hearts via the pericardial cavity. The results of reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting analyses demonstrated that cardiac β1-AR expression in the rAAV9-Adrb1 group was significantly downregulated when compared with the rAAV9-NC group (P<0.001, P<0.001 and P=0.032, respectively). In addition, a greater reduction in systolic blood pressure (SBP) was observed in the rAAV9-NC group compared with the rAAV9-Adrb1 group following Met treatment (P=0.035). Furthermore, downregulation of myocardial β1-AR was associated with a significant decrease in SBP (P<0.001). In conclusion, these data suggest that suppression of β1-AR expression in the myocardium reduces SBP and sensitivity to Met in SHR.

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Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to β-blocker therapy in hypertension

Cited by 29 publications

References 39 publications

Pharmacokinetic Parameters and Over-Responsiveness of Iranian Population to Propranolol

Pharmacokinetic Parameters and Over-Responsiveness of Iranian Population to Propranolol

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

Downregulation of the β1 adrenergic receptor in the myocardium results in insensitivity to metoprolol and reduces blood pressure in spontaneously hypertensive rats

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