School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
College of Pharmacy, Dankook University, Cheonan, 31116, Republic of Korea.
Arch Pharm Res. 2023 May;46(5):438-447. doi: 10.1007/s12272-023-01448-z. Epub 2023 Apr 25.
Gliclazide metabolism is mediated by genetically polymorphic CYP2C9 and CYP2C19 enzymes. We investigated the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide. Twenty-seven Korean healthy volunteers were administered a single oral dose of gliclazide 80 mg. The plasma concentration of gliclazide was quantified for the pharmacokinetic analysis and plasma concentrations of glucose and insulin were measured as pharmacodynamic parameters. The pharmacokinetics of gliclazide showed a significant difference according to the number of defective alleles of combined CYP2C9 and CYP2C19. The two defective alleles group (group 3) and one defective allele group (group 2) showed 2.34- and 1.46-fold higher AUC (P < 0.001), and 57.1 and 32.3% lower CL/F (P < 0.001), compared to those of the no defective allele group (group 1), respectively. The CYP2C9IM-CYP2C19IM group had AUC increase of 1.49-fold (P < 0.05) and CL/F decrease by 29.9% (P < 0.01), compared with the CYP2C9 Normal Metabolizer (CYP2C9NM)-CYP2C19IM group. The CYP2C9NM-CYP2C19PM group and CYP2C9NM-CYP2C19IM group showed 2.41- and 1.51-fold higher AUC (P < 0.001), and 59.6 and 35.4% lower CL/F (P < 0.001), compared to those of the CYP2C9NM-CYP2C19NM group, respectively. The results represented that CYP2C9 and CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of gliclazide. Although the genetic polymorphism of CYP2C19 had a greater effect on the pharmacokinetics of gliclazide, the genetic polymorphism of CYP2C9 also had a significant effect. On the other hand, plasma glucose and insulin responses to gliclazide were not significantly affected by the CYP2C9-CYP2C19 genotypes, requiring further well-controlled studies with long-term dosing of gliclazide in diabetic patients.
格列齐特的代谢由遗传多态性 CYP2C9 和 CYP2C19 酶介导。我们研究了 CYP2C9 和 CYP2C19 遗传多态性对格列齐特药代动力学和药效学的影响。27 名韩国健康志愿者单次口服格列齐特 80mg。进行药代动力学分析时定量测定格列齐特的血浆浓度，作为药效学参数测量血浆葡萄糖和胰岛素浓度。格列齐特的药代动力学表现出与联合 CYP2C9 和 CYP2C19 缺陷等位基因数量显著差异。两个缺陷等位基因组（组 3）和一个缺陷等位基因组（组 2）的 AUC 分别增加 2.34 倍和 1.46 倍（P<0.001），CL/F 分别降低 57.1%和 32.3%（P<0.001），与无缺陷等位基因组（组 1）相比。CYP2C9IM-CYP2C19IM 组的 AUC 增加 1.49 倍（P<0.05），CL/F 降低 29.9%（P<0.01），与 CYP2C9 正常代谢物（CYP2C9NM）-CYP2C19IM 组相比。CYP2C9NM-CYP2C19PM 组和 CYP2C9NM-CYP2C19IM 组的 AUC 分别增加 2.41 倍和 1.51 倍（P<0.001），CL/F 分别降低 59.6%和 35.4%（P<0.001），与 CYP2C9NM-CYP2C19NM 组相比。结果表明，CYP2C9 和 CYP2C19 遗传多态性显著影响格列齐特的药代动力学。虽然 CYP2C19 的遗传多态性对格列齐特的药代动力学有更大的影响，但 CYP2C9 的遗传多态性也有显著的影响。另一方面，CYP2C9-CYP2C19 基因型对格列齐特的血浆葡萄糖和胰岛素反应没有显著影响，需要在糖尿病患者中进行更长时间的格列齐特给药的对照良好的研究。
