School of Pharmacy, National Defense Medical Center, P.O. Box 90048-512, Taipei, Taiwan, Republic of China.
AAPS J. 2014 Mar;16(2):206-13. doi: 10.1208/s12248-013-9535-x. Epub 2013 Dec 20.
To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25% ∼ 64%), increased area under the plasma level-time curves (30~76%), increased area under the time infinity (43% ∼ 80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.
为了了解台湾人群的遗传背景和对药代动力学（PK）的影响，我们分析了药物遗传学（PG）谱，并以吲达帕胺为例展示了其对酶代谢的影响。我们采用多重质谱法检测了 1038 名台湾受试者中 8 种主要 I 相和 II 相代谢酶的单核苷酸多态性（SNP）谱。在 24 名健康受试者中进行了 PG/PK 研究，以研究 28 个 SNP 对药物生物转化的可能影响。在所分析的遗传图谱中，来自 CYP2A6、CYP2C19、CYP2D6、CYP2E1、CYP3A5 和 UGT2B7 的 8 个 SNP 的变异频率高于先前在白种人和非洲人报告的频率。例如，我们观察到 CYP2A6 中的 SNP rs5031016（I471T）在台湾人群中的频率为 14.7%，而白种人和非洲人群中则没有变异。吲达帕胺的 PG/PK 研究表明，多态性 SNP CYP2C9 rs4918758 和 CYP2C19 rs4244285 似乎赋予了较低的酶活性，表现为 Cmax 增加（25%64%）、血浆水平时间曲线下面积增加（3076%）、时间无穷大下面积增加（43%~80%）和表观清除率值降低，低于野生型吲达帕胺的 PK 值。我们的结果强化了 CYP2C19 在吲达帕胺代谢中的生化支持，并确定了一种可能的新参与酶 CYP2C9。PG/PK 方法有助于了解不同人群的遗传背景和药物代谢中酶的关联。它可以用于识别两个遗传标记，能够区分吲达帕胺 PK 结果不同的受试者。
