Yin Ophelia Q P, Tomlinson Brian, Chow Moses S S
School of Pharmacy and Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong.
Clin Pharmacol Ther. 2005 Oct;78(4):370-7. doi: 10.1016/j.clpt.2005.06.006.
Although cytochrome P450 (CYP) 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.
Three groups of healthy male Chinese subjects (n=6 per group) were enrolled, as follows: group I, CYP2C9*1/1 and CYP2C19 extensive metabolizers (EMs); group II, CYP2C91/1 and CYP2C19 poor metabolizers (PMs); and group III, CYP2C91/*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.
No significant differences in glyburide pharmacokinetics were observed between CYP2C19 EM and PM subjects who had the CYP2C9*1/1 genotype (group I versus group II). Their respective values for area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity) and elimination half-life (t1/2) were 0.46+/-0.13 microg.h/mL versus 0.57+/- 0.11 microg.h/mL (P=.569) and 2.09+/-0.22 hours versus 2.24+/- 0.27 hours (P=.721). 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 CYP2C91/3 subjects (group III) were compared with CYP2C91/1 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 CYP2C91/3 carriers and 2 of 12 CYP2C91/*1 carriers.
CYP2C9, but not CYP2C19, 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.
尽管细胞色素P450（CYP）2C9被认为是格列本脲（国际非专利药品名称，优降糖）体内代谢的主要途径，但体外研究表明CYP2C19具有更显著的作用。本研究调查了CYP2C9和CYP2C19基因型对中国受试者中格列本脲药代动力学和药效学的相对影响。
招募了三组健康中国男性受试者（每组n = 6），如下：第一组，CYP2C9*1/1和CYP2C19广泛代谢者（EMs）；第二组，CYP2C91/1和CYP2C19慢代谢者（PMs）；第三组，CYP2C91/*3和CYP2C19 EMs。受试者单次口服5 mg格列本脲。采集多份血样，采用高效液相色谱法测定血浆格列本脲浓度。给药后2小时内还测量了血浆葡萄糖和胰岛素浓度。
具有CYP2C9*1/1基因型的CYP2C19 EM和PM受试者之间（第一组与第二组），格列本脲药代动力学未观察到显著差异。其各自的从0至无穷大的血浆浓度-时间曲线下面积（AUC0-无穷大）和消除半衰期（t1/2）值分别为0.46±0.13μg·h/mL对0.57±0.11μg·h/mL（P = 0.569）以及2.09±0.22小时对2.24±0.27小时（P = 0.721）。然而，当将CYP2C91/3受试者（第三组）与第一组或第二组中的CYP2C91/1受试者进行比较时，观察到AUC(0-无穷大)（分别增加125%和82%；P = 0.008和0.024）和t1/2（分别增加71%和60%；P = 0.003和0.007）有显著升高。给药后2小时的血糖降低分别为第一组41.8%、第二组23.9%和第三组27.7%（P = 0.029），6名CYP2C91/3携带者中有3人发生低血糖，12名CYP2C91/*1携带者中有2人发生低血糖。
CYP2C9而非CYP2C19的多态性似乎对体内格列本脲的药代动力学和药效学起主要影响。有必要对糖尿病患者进行长期给药的进一步研究以证实这些发现。
