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Influence of phenotype and pharmacokinetics on β-blocker drug target pharmacogenetics

Abstract

Two common polymorphisms in the β1-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 (82±10 versus 74±11 bpm, respectively, P=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 (0.75±0.11 versus 0.57±0.17%/ng/ml, respectively, P=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=0.05). Our data suggest that neither the β1-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.

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Acknowledgements

We would like to gratefully acknowledge Kathy Eberst for her expert HPLC analytic assistance and Dr Hartmut Derendorf for his insightful comments regarding the manuscript. This study was supported by NIH Grants HL64691, HL68834, and by the University of Florida GCRC Grant RR00082.

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Correspondence to J A Johnson.

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The study sponsor had no involvement in study design, data collection, analysis, or interpretation, writing of the paper, or the decision to submit the paper for publication.

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Beitelshees, A., Zineh, I., Yarandi, H. et al. Influence of phenotype and pharmacokinetics on β-blocker drug target pharmacogenetics. Pharmacogenomics J 6, 174–178 (2006). https://doi.org/10.1038/sj.tpj.6500354

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