Jiang Zhi-Ping, Shu Yan, Chen Xiao-Ping, Huang Song-Lin, Zhu Rong-Hua, Wang Wei, He Nan, Zhou Hong-Hao
Pharmacogenetics Research Institute, Xiang-Ya School of Medicine, Central South University, Changsha 410078, China.
Eur J Clin Pharmacol. 2002 May;58(2):109-13. doi: 10.1007/s00228-002-0445-6. Epub 2002 Apr 11.
To determine the role of cytochrome P(450) (CYP)2C19 in N-demethylation of amitriptyline (AT) in healthy Chinese subjects.
One hundred and one subjects were genotyped for CYP2C19 using polymerase chain reaction-restriction fragment length polymorphism analysis. Twelve unrelated adult men (19.7+/-0.6 years, 61.8+/-3.8 kg) were chosen and orally given a single dose of 50 mg AT, and the blood samples were drawn from a forearm vein at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h after AT administration. Plasma concentrations of AT and nortriptyline (NT) were determined using high-performance liquid chromatography with an ultraviolet detector.
The mean area under the plasma concentration-time curve (AUC(AT)) of CYP2C19 poor metabolizers (PMs, n=6) was significantly higher than that of CYP2C19 extensive metabolizers (EMs, n=6) (2207+/-501 ng/ml x h(-1) vs 1596+/-406 ng/ml x h(-1), P<0.05). In contrast, the mean AUC(NT(0-)(infinity)()) of PMs was significantly lower than that of EMs (294+/-70 ng/ml x h(-1) vs 684+/-130 ng/ml x h(-1), P<0.0001). Other pharmacokinetic parameters such as clearance, half-life, maximum plasma concentration, and time to peak plasma concentration showed no significant difference between PMs and EMs (0.41+/-0.12 l /h x kg(-1) vs 0.50+/-0.15 l /h x kg(-1), 25.0+/-6.2 h vs 24.1+/-4.4 h, 96+/-25 ng/ml vs 75+/-27 ng/ml, 4.0+/-1.4 h vs 3.7+/-1.5 h, respectively).
The genetic defects of CYP2C19 have a significant effect on AT pharmacokinetics, and CYP2C19 plays an important role in N-demethylation of AT in vivo at a clinically therapeutic dose.
确定细胞色素P(450)(CYP)2C19在中国健康受试者中对阿米替林（AT）N-去甲基化的作用。
采用聚合酶链反应-限制性片段长度多态性分析对101名受试者进行CYP2C19基因分型。选取12名无关成年男性（19.7±0.6岁，61.8±3.8 kg），口服单剂量50 mg AT，并于AT给药后0.5、1、2、3、4、5、6、8、10、12、24、48、72和96小时从前臂静脉采集血样。采用高效液相色谱-紫外检测器测定血浆中AT和去甲替林（NT）的浓度。
CYP2C19慢代谢者（PMs，n = 6）的血浆浓度-时间曲线下平均面积（AUC(AT)）显著高于CYP2C19快代谢者（EMs，n = 6）（2207±501 ng/ml·h⁻¹ 对1596±406 ng/ml·h⁻¹，P<0.05）。相反，PMs的平均AUC(NT(0-)(infinity)())显著低于EMs（294±70 ng/ml·h⁻¹ 对684±130 ng/ml·h⁻¹，P<0.0001）。其他药代动力学参数，如清除率、半衰期、最大血浆浓度和血浆浓度达峰时间，PMs和EMs之间无显著差异（分别为0.41±0.12 l/h·kg⁻¹ 对0.50±0.15 l/h·kg⁻¹，25.0±6.2 h对24.1±4.4 h, 96±25 ng/ml对75±27 ng/ml, 4.0±1.4 h对3.7±1.5 h）。
CYP2C19的基因缺陷对AT的药代动力学有显著影响，且CYP2C19在临床治疗剂量下对体内AT的N-去甲基化起重要作用。
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