Abstract
Purpose: This study was performed to investigate the effects of common polymorphisms in CYP2D6 and CYP3A5 on the plasma concentrations and antihypertensive effects of bisoprolol in hypertensive Chinese patients.Methods: One hundred patients with essential hypertension were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Clinic blood pressure (BP) and ambulatory BP (ABP) were measured after the placebo run-in and after 6 weeks treatment. Peak plasma concentrations of bisoprolol were measured at 3 h after the first dose and 3 h after the dose after 6 weeks treatment. Trough levels were measured before the dose after 6 weeks treatment. Bisoprolol plasma concentrations were measured with a validated liquid chromatography tandem mass spectrometry method. Six common polymorphisms in CYP2D6 and the CYP3A5*3 polymorphism were genotyped by TaqMan® assay.Results: After 6 weeks of treatment, clinic BP and heart rate were significantly reduced by 14.3 ± 10.9/8.4 ± 6.2 mmHg (P < 0.01) and 6.3 ± 7.6 BPM (P < 0.01), respectively. Similar reductions were seen in ABP values. Bisoprolol plasma concentration at 3 h after the first dose and 3 h post-dose after 6 weeks of treatment were significantly associated with baseline body weight (P < 0.001) but there was no significant effect of the CYP2D6 and CYP3A5 polymorphisms on these or the trough plasma concentrations. There was no significant association of the CYP2D6 and CYP3A5 polymorphisms or plasma bisoprolol concentrations with the clinic BP or ABP responses to bisoprolol.Conclusion: Bisoprolol 2.5 mg daily effectively reduced BP and HR. The common polymorphisms in CYP2D6 that were examined and the CYP3A5*3 polymorphism appear to have no benefit in predicting the hemodynamic response to bisoprolol in these patients.
Highlights
Hypertension is the leading preventable cause of death globally, but there are major disparities of hypertension prevalence, awareness, treatment, and control in different countries [1]
Several β-blockers, in particular metoprolol, are extensively metabolized by cytochrome P450 2D6 (CYP2D6) and the CYP2D6 genotype has a pronounced effect on the single dose pharmacokinetics of metoprolol which persists during long-term therapy [8]
A more recent metaanalysis of 15 studies found that CYP2D6 poor metabolizers (PM) had significantly greater reductions in heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared to non-PM individuals [10]
Summary
Hypertension is the leading preventable cause of death globally, but there are major disparities of hypertension prevalence, awareness, treatment, and control in different countries [1]. Betaadrenoceptor antagonists or β-blockers are one of the oldest groups of drugs used to treat hypertension, recent guidelines from the U.S and Europe no longer recommend them as first line treatment for hypertension unless there are additional indications such as heart failure or post-myocardial infarction [2, 3]. This advice is based on a meta-analysis which reported an increased risk of stroke with the use of β-blockers compared with other antihypertensive agents [4]. A more recent metaanalysis of 15 studies found that CYP2D6 poor metabolizers (PM) had significantly greater reductions in HR, SBP and DBP compared to non-PM individuals [10]
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