Saiz-Rodríguez Miriam, Almenara Susana, Navares-Gómez Marcos, Ochoa Dolores, Román Manuel, Zubiaur Pablo, Koller Dora, Santos María, Mejía Gina, Borobia Alberto M, Rodríguez-Antona Cristina, Abad-Santos Francisco
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, Spain.
Reseach Unit, Fundación Burgos por la Investigación de la Salud, Hospital Universitario de Burgos, 09006 Burgos, Spain.
Biomedicines. 2020 Apr 22;8(4):94. doi: 10.3390/biomedicines8040094.
Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for and polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither phenotype nor individual or polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC ( = 0.099) and a tendency of lower normalized Cl ( = 0.069) in mutated allele carriers what was associated with diminished drug metabolism capacity. polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme.
几种细胞色素P450（CYP）CYP3A基因多态性与酶功能降低有关。我们旨在评估这些等位基因对几种CYP3A底物药代动力学参数（PK）的影响。我们纳入了251名健康志愿者，他们接受了单剂量的安立生坦、阿托伐他汀、伊马替尼、阿立哌唑、芬太尼、氨氯地平、多奈哌齐、奥氮平、非索罗定或喹硫平。通过qPCR对志愿者进行了 和 基因多态性的基因分型。为了比较不同研究中的PK，测量值通过每种药物各参数的平均值进行校正，并进行对数转换。 表型、个体 或 基因多态性均与PK差异无显著相关性。然而，对于仅由CYP3A代谢的底物，我们观察到 突变等位基因携带者的标准化AUC较高（ = 0.099），标准化Cl有降低的趋势（ = 0.069），这与药物代谢能力降低有关。 基因多态性对所分析药物的PK没有明显影响。如果有影响，在极少数受试者中可能检测到。虽然携带CYP3A4双突变的受试者很少，但在这些受试者中的影响可能是显著的，特别是由于大多数受试者缺乏CYP3A5酶。在杂合子受试者中，由于CYP3A4酶的高诱导潜力，其后果可能不太明显。
