Effects ofβ1-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy

Abstract

Abstract: BACKGROUND: Metoprolol is a selectiveβ₁-Blocker commonly used in essentiaL/hypertension. It is metabolized by CYP2D6.CYP2D6 *10, which was identified to decrease activity of CYP2D6, is the main variance in Chinese population.β1-adrenergic receptor, with Ser49Gly and Gly389Arg polymorphisms, is the target of metoprolol.It was still unknown that whether the CYP2D6 andβ₁-adrenergic receptor had a synergic effect on metoprolol antihypertension therapy. AIM: To clarify the genetic polymorphism associated with metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy. METHODS: 125 mild-to-med essentiaL/hypertension patients were enrolled in this study.Patients were mono-therapied with metoprolol for 12 weeks.Blood pressure was monitored every 4 weeks.PCR-RFLP method was use to identify CYP2D6 *10 andβ₁-adrenergic receptor Ser49Gly and Gly389Arg polymorphisms.Plasma metoprolol concentration was measured by HPLC- fluorescence detection. RESULTS: Trough blood level (C0)of metoprolol was associated with CYP2D6 *10 variance in a gene-dose-effect manner, whereas the extent of blood pressure decrease was not significant different in CYP2D6 *1 *1, *1 *10 and CYP2D6 *10 *10 patients. After 12 weeks metoprolol therapy, Gly49 carriers had stronger decrease in systolic and diastolic blood pressure than that of Ser49 homozygotes.Similarly, subjects homozygous for Arg389 had stronger decrease in blood pressure than that of Gly389 carriers.CONCLUSION: CYP2D6 *10 variance significantly change the pharmacokinetics of metoprolol, and the genetic polymorphisms of β₁-adrenergic receptorwere associated with the pharmacodynamics of metopolol in antihypertension therapy.

Key words: CYP2D6, β1-adenergic receptor, genetic polymorphism, essentiaL/hypertension, metoprolol

LIU Jie, LIU Zhao-qian, LIU Ying-zi, TAN Zhi-rong, HU Dong-li, LI Zhi, WANG Dan, ZHANG Wei, ZHOU Hong-hao. Effects ofβ₁-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(10): 1130-1137.

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Effects ofβ₁-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy

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