Park Jin-Woo, Chung Hyewon, Kim Kyoung-Ah, Kim Jong-Min, Park In-Hwan, Lee Sangjin, Park Ji-Young
Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Korea.
Department of Clinical Pharmacology and Toxicology, Guro Hospital, Korea University College of Medicine, Seoul, Korea.
Front Pharmacol. 2021 Apr 29;12:658039. doi: 10.3389/fphar.2021.658039. eCollection 2021.
Imatinib is transported extracellularly by ABCB1 and ABCG2 efflux transporters and bound to alpha-1-acid glycoprotein (AGP) in the bloodstream. However, the clinical and pharmacokinetic effects of ABCB1 and ABCG2 on imatinib were inconsistent in the previous literature and have not been confirmed. Therefore, in the present study, we explored the effects of the and genetic polymorphisms on imatinib pharmacokinetics in association with plasma AGP levels in healthy subjects. Twenty-seven healthy individuals were recruited, genotyped for and , and given a single oral dose of 400 mg imatinib. Plasma imatinib concentrations were measured and its pharmacokinetics was assessed with respect to (c.421C>A and c.34G>A) and (c.1236C>T, c.2677C>T/A, and c.3435C>T) genotypes, and plasma AGP levels. AGP levels showed a strong positive correlation with imatinib pharmacokinetics. ABCG2 c.421C>A single nucleotide polymorphism showed a statistically significant effect on imatinib pharmacokinetics in low plasma AGP levels groups (<80 mg/dl); subjects with high plasma AGP levels (n = 5, ≥80 mg/dl) were excluded. The results indicate that plasma AGP levels and polymorphisms modulated imatinib pharmacokinetics; however, the effects of the ABCG2 transporter was masked at high plasma AGP levels.
伊马替尼通过ABCB1和ABCG2外排转运蛋白转运至细胞外，并在血液中与α-1-酸性糖蛋白（AGP）结合。然而，ABCB1和ABCG2对伊马替尼的临床和药代动力学影响在以往文献中并不一致，尚未得到证实。因此，在本研究中，我们探讨了ABCB1和ABCG2基因多态性对健康受试者伊马替尼药代动力学的影响，并与血浆AGP水平相关联。招募了27名健康个体，对ABCB1和ABCG2进行基因分型，并给予单次口服400 mg伊马替尼。测量血浆伊马替尼浓度，并根据ABCB1（c.421C>A和c.34G>A）和ABCG2（c.1236C>T、c.2677C>T/A和c.3435C>T）基因型以及血浆AGP水平评估其药代动力学。AGP水平与伊马替尼药代动力学呈强正相关。ABCG2 c.421C>A单核苷酸多态性在低血浆AGP水平组（<80 mg/dl）对伊马替尼药代动力学有统计学显著影响；排除血浆AGP水平高的受试者（n = 5，≥80 mg/dl）。结果表明，血浆AGP水平和ABCB基因多态性调节了伊马替尼的药代动力学；然而，在高血浆AGP水平时，ABCG2转运蛋白的作用被掩盖。
