CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects
CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects
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DOI：
10.1016/j.clpt.2005.06.006
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发表时间：
2005-10-01
影响因子：
6.7
通讯作者：
Chow, MSS
中科院分区：
文献类型：
--
作者：
Yin, OQP;Tomlinson, B;Chow, MSS
背景资料：虽然细胞色素P450（CY-P）2C 9被认为是格列本脲（INN，格列本脲）体内代谢的主要途径，但体外研究表明CYP 2C 19具有更主导的作用。本研究探讨了中国受试者中CYP 2C 9和CYP 2C 19基因型对格列本脲药代动力学和药效学的相对影响。（每组n = 6），如下：组1，CYP 2C 9 *1/*1和CYP 2C 19快代谢型（EM）;组II，CYP 2C 9 *1/*1和CYP 2C 19弱代谢型（PM）; Ⅲ组为CYP 2C 9 *1/*3和CYP 2C 19 EM。受试者接受5 mg格列本脲单次口服给药。采集多份血样，采用HPLC法测定格列本脲血药浓度。血浆葡萄糖和胰岛素浓度也测量了2小时后dosing.Results：没有显着差异格列本脲的药代动力学之间观察到CYP 2C 19 EM和PM受试者谁有C γ P2 C9 *1/*1基因型（组I与组II）。从时间0至无穷大的血药浓度-时间曲线下面积的相应值AUC（0-无穷大）和消除半衰期（t1/2）分别为0.46 +/- 0.13 μ g中心点h/mL和0.57 +/- 0.11 μ g中心点h/mL（P =.569）和2.09 +/- 0.22小时对2.24 +/- 0.27小时（P =.72）。然而，当C γ P2 C9 *1/*3受试者（组III）与组I或组II中的C γ P2 C9 *1/*1受试者相比时，观察到AUC（0-无穷大）（分别为125%和82%; P = 0.008和0.024）和t1/2（分别为71%和60%; P = 0.003和0.007）显著增加。给药后2小时，组I、II和III的血糖降幅分别为41.8%、23.9%和27.7%（P = 0.029），并且在6名C γ P2 C9 *1/*3携带者中的3名和12名C γ P2 C9 *1/*1携带者中的2名中发生低血糖。CYP 2C 9（而非CYP 2CI 9）多态性似乎对格列本脲的体内药代动力学和药效学产生了主要影响。需要在长期给药的糖尿病患者中进行进一步研究以证实这些发现。
Background: Although cytochrome P450 (CY-P) 2C9 was thought to be the main pathway for glyburide (INN, glibenclamide) metabolism in vivo, studies in vitro indicated that CYP2C19 had a more dominant effect. This study investigated the relative influence of CYP2C9 and CYP2C19 genotypes on the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects.Methods: Three groups of healthy male Chinese subjects (n = 6 per group) were enrolled, as follows: group 1, CYP2C9*1/*1 and CYP2CI9 extensive metabolizers (EMs); group II, CYP2C9*1/*1 and CYP2CI9 poor metabolizers (PMs); and group III, CYP2C9*1/*3 and CYP2C19 EMs. Subjects received single oral doses of 5 mg glyburide. Multiple blood samples were collected, and the plasma glyburide concentrations were determined by an HPLC method. The plasma glucose and insulin concentrations were also measured up to 2 hours after dosing.Results: No significant differences in glyburide pharmacokinetics were observed between CYP2C19 EM and PM subjects who had the C gamma P2C9*1/*1 genotype (group I versus group II). Their respective values for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) and elimination half-life (t1/2) were 0.46 +/- 0.13 mu g center dot h/mL versus 0.57 +/- 0.11 mu g center dot h/mL (P =.569) and 2.09 +/- 0.22 hours versus 2.24 +/- 0.27 hours (P =.72). However, significant increases in AUC(0-infinity), (125% and 82%; P =.008 and .024, respectively) and t1/2 (71% and 60%; P =.003 and .007, respectively) were observed when C gamma P2C9*1/*3 subjects (group III) were compared with C gamma P2C9*1/*1 subjects in group I or II. Blood glucose reductions at 2 hours after dosing were 41.8%, 23.9%, and 27.7% in groups I, II, and III, respectively (P =.029), and hypoglycemia developed in 3 of 6 C gamma P2C9*1/*3 carriers and 2 of 12 C gamma P2C9*1/*1 carriers.Conclusion: CYP2C9, but not CYP2CI9, polymorphism appears to exert a dominant influence on glyburide pharmacokinetics; and pharmacodynamics in vivo. Further studies in diabetic patients with long-term dosing are warranted to confirm these findings.