Effects of β1-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy
- VernacularTitle:β1肾上腺素受体与CYP2D6基因多态性对美托洛尔抗高血压治疗的药代动力学和药效学影响
- Author:
Jie LIU
;
Zhaoqian LIU
;
Yingzi LIU
;
Zhirong TAN
;
Dongli HU
;
Zhi LI
;
Dan WANG
;
Wei ZHANG
;
Honghao ZHOU
- Publication Type:Journal Article
- Keywords:
CYP2D6;
β1-adenergic receptor;
genetic polymorphism;
essential hypertension;
metoprolol
- From:
Chinese Journal of Clinical Pharmacology and Therapeutics
2007;12(10):1130-1137
- CountryChina
- Language:Chinese
-
Abstract:
BACKGROUND: Metoprolol is a selective β1-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 and β1-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 and β1-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 receptor were associated with the pharmacodynamics of metopolol in antihypertension therapy.
