Forensic Medicine Service, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon, Mexico.
Analytical Department of the Research Institute for Clinical and Experimental Pharmacology, Ipharma S.A, Monterrey, Nuevo Leon, Mexico.
Sci Rep. 2019 Nov 28;9(1):17833. doi: 10.1038/s41598-019-54436-z.
Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. Nonetheless, studies on interindividual pharmacokinetic variability and its association with genetic variants are limited. We employed a pharmacokinetic and pharmacogenetic approach to determine possible metabolic phenotypes of AFP and identify genetic markers that could affect the pharmacokinetic variability in a Mexican population. A controlled, randomized, crossover, single-blind, two-treatment, two-period, and two sequence clinical study of AFP (a single 75 mg dose) was conducted in 36 healthy Mexican volunteers who fulfilled the study requirements. Amfepramone plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed using real-time PCR with TaqMan probes. Four AFP metabolizer phenotypes were found in our population: slow, normal, intermediate, and fast. Additionally, two gene polymorphisms, ABCB1-rs1045642 and CYP3A4-rs2242480, had a significant effect on AFP pharmacokinetics (P < 0.05) and were the predictor factors in a log-linear regression model. The ABCB1 and CYP3A4 gene polymorphisms were associated with a fast metabolizer phenotype. These results suggest that metabolism of AFP in the Mexican population is variable. In addition, the genetic variants ABCB1-rs1045642 and CYP3A4-rs2242480 may partially explain the AFP pharmacokinetic variability.
苯丁胺（AFP）是一种用于治疗肥胖症的食欲抑制剂药物。然而，个体间药代动力学变异性及其与遗传变异的相关性研究有限。我们采用药代动力学和遗传药理学方法来确定 AFP 的可能代谢表型，并确定可能影响墨西哥人群药代动力学变异性的遗传标记。在 36 名符合研究要求的健康墨西哥志愿者中进行了一项 AFP（单次 75mg 剂量）的对照、随机、交叉、单盲、两治疗、两期和两序列临床研究。使用高效液相色谱-质谱法测量 AFP 血浆水平。使用实时 PCR 与 TaqMan 探针进行基因分型。在我们的人群中发现了四种 AFP 代谢表型：慢代谢型、正常代谢型、中间代谢型和快代谢型。此外，ABCB1-rs1045642 和 CYP3A4-rs2242480 两个基因多态性对 AFP 药代动力学有显著影响（P<0.05），并在对数线性回归模型中是预测因素。ABCB1 和 CYP3A4 基因多态性与快代谢表型相关。这些结果表明，AFP 在墨西哥人群中的代谢是可变的。此外，遗传变异 ABCB1-rs1045642 和 CYP3A4-rs2242480 可能部分解释了 AFP 药代动力学的变异性。
