人类交感激活alpha2-adrenergic封锁和育亨宾:双峰,上位性细胞色素P450-mediated药物代谢的影响。

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Le来往P及parm RJ Kailasam MT,肯尼迪BP, Skaar TP,何鸿燊H, Leverge R,史密斯DW,齐格勒MG, Insel PA,肖克新泽西,弗洛克哈特哒,奥康纳DT

人类交感激活alpha2-adrenergic封锁和育亨宾:双峰,上位性细胞色素P450-mediated药物代谢的影响。

中国新药杂志。2004年8月,76(2):139 - 53年。doi: 10.1016 / j.clpt.2004.04.010。

PubMed ID

15289791 (在PubMed

]

文摘

背景:alpha2-Adrenergic封锁反应建议高血压的肾上腺素的障碍。alpha2-Blockade也用于治疗自主神经功能障碍。然而,药代动力学因素育亨宾的性格并不理解。评估方法:我们在172年与静脉育亨宾alpha2-blockade个人。特定的细胞色素P450 (CYP) isoform-mediated代谢研究。结果评估通过方差分析和最大似然分析分布为双峰性反应。结果:育亨宾新陈代谢11-hydroxy-yohimbine显示大于1000倍的变化,与17个人没有新陈代谢。Nonmetabolizers不同于其他种族但不是在年龄、性别、身体体质,血压、心率、或高血压家族史。新陈代谢是由频率直方图的双峰性,以及最大似然和聚类分析。在少数民族中,受试者的欧洲祖先nonmetabolism频率最高。 In vitro oxidation suggested that the major route of metabolism (lowest Michaelis-Menten constant and greatest intrinsic clearance) was likely via CYP2D6 to 11-hydroxy-yohimbine. In vivo genotypes at both CYP2D6 and CYP3A4 were necessary to predict metabolism (overall F = 3.03, P =.005); an interaction of alleles at these 2 loci (interaction F = 3.05, P =.033) suggested an epistatic effect on drug metabolism in vivo. Nonmetabolizers had greater activation of sympathetic nervous system activity. Yohimbine increased blood pressure, an effect mediated hemodynamically by elevation of cardiac output rather than systemic vascular resistance. Blood pressure and cardiac output responses did not differ by metabolizer group. CONCLUSIONS: We conclude that heterogeneous, bimodally distributed yohimbine metabolism depends on common genetic variation in both CYP2D6 and CYP3A4 and contributes to differences in sympathetic neuronal response to alpha2-blockade. These results have implications for both diagnostic and therapeutic uses of this alpha2-antagonist.

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药物酶

药物	酶	类	生物	药理作用	行动
育亨宾	细胞色素P450 2 d6	蛋白质	人类	未知的	底物	细节
育亨宾	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节