Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers
Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers
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DOI：
10.1067/mcp.2002.122476
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发表时间：
2002-04-01
影响因子：
6.7
通讯作者：
Roots, I
中科院分区：
文献类型：
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作者：
Kirchheiner, J;Brockmöller, J;Roots, I
背景：格列本脲(格列本脲，格列本脲)是第二代高效磺脲类降糖药。我们推测格列本脲可能是细胞色素P450 2C9(细胞色素P450 2C9)的底物，细胞色素P450 2C9是一种具有两个低活性氨基酸变体-Arg144Cys(CYP2C9*2)和Ile359Leu(CYP2C9*3)的酶。我们探讨了这些基因多态性对格列本脲药代动力学的影响以及对胰岛素和血糖浓度的影响。方法：对21名健康志愿者进行研究，他们代表了两个变异等位基因的所有可能组合(基因类型为*1/*1、*1/*2、*2/*2、*1/*3、*2/*3和*3/*3)。他们在服用格列本脲1、4.5和8小时后，单次口服3.5毫克格列本脲，然后再服用75克葡萄糖。用反相高效液相色谱法测定格列本脲的血药浓度。用NONMEM统计软件对格列本脲、胰岛素和葡萄糖的静脉血药浓度进行群体药代动力学-药效学模型分析。结果：格列本脲的药代动力学显著依赖于CYP2C9基因。在*3/*3纯合子携带者中，总口腔清除量不到野生型*1/*1的一半(P
Background: Glyburide (INN, glibenclamide) is a second-generation sulfonylurea antidiabetic agent with high potency. We hypothesized that glyburide may be a substrate of cytochrome P450 2C9 (CYP2C9), an enzyme that has two low-activity amino acid variants-Arg144Cys (CYP2C9*2) and Ile359Leu (CYP2C9*3). We explored the impact of these polymorphisms on glyburide pharmacokinetics and the effects on insulin and glucose concentrations.Methods: Twenty-one healthy volunteers who represented all possible combinations of the two variant alleles were studied (genotypes CYP2C9*1/*1, *1/*2, *2/*2, *1/*3, *2/*3, and *3/*3). They received a single oral dose of 3.5 mg glyburide followed by 75 g glucose at 1, 4.5, and 8 hours after administration of glyburide. Glyburide was quantified in plasma by reversed-phase HPLC. Venous blood concentrations of glyburide, insulin, and glucose were analyzed with a population pharmacokinetic-pharmacodynamic model by use of NONMEM statistical software.Results: Pharmacokinetics of glyburide depended significantly on CYP2C9 genotypes. In homozygous carriers of the genotype *3/*3, total oral clearance was less than half of that of the wild-type genotype *1/*1 (P