Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Cancer Chemother Pharmacol. 2011 Oct;68(4):1093-8. doi: 10.1007/s00280-011-1715-8. Epub 2011 Jul 31.
Atrasentan is a highly potent and selective endothelin receptor A (ET(A)) antagonist under development for the treatment of prostate cancer. Only little data exist on its interaction with drug-metabolising enzymes and drug transporters possibly influencing its safety and effectiveness. Our study evaluated whether atrasentan can induce the expression of relevant human drug transporters and cytochrome P450 isozymes (CYPs), whether it retains its efficiency in multidrug resistant cell lines, and whether it inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Induction of transporters and enzymes was quantified at the mRNA level by real-time RT-PCR in LS180 cells and for P-gp also at the protein level by Western blot. P-gp inhibition was evaluated by calcein assay in P388/dx and L-MDR1 cells and BCRP inhibition in MDCKII-BCRP cells by pheophorbide A efflux. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC-transporters.
Atrasentan profoundly induced several CYPs and drug transporters (e.g. 12-fold induction of CYP3A4 at 50 μM). It was a moderate P-gp inhibitor (IC(50) in P388/dx cells = 15.1 ± 1.6 μM) and a weak BCRP inhibitor (IC(50) in MDCKII-BCRP cells = 59.8 ± 11 μM). BCRP or P-gp overexpressing cells were slightly more resistant towards antiproliferative effects of atrasentan.
Our data provide a comprehensive analysis of the induction profile of atrasentan and its interaction with P-gp and BCRP. The profound induction effects stress the need for thorough assessment of its interaction potential in vivo.
阿特森坦是一种高效且选择性的内皮素受体 A（ET(A)）拮抗剂，目前正在开发用于治疗前列腺癌。关于其与代谢药物的酶和药物转运体的相互作用的相关数据很少，这可能会影响其安全性和有效性。我们的研究评估了阿特森坦是否可以诱导相关的人药物转运体和细胞色素 P450 同工酶（CYPs）的表达，它在多药耐药细胞系中是否仍然有效，以及它是否抑制 P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）。
通过实时 RT-PCR 在 LS180 细胞中定量测定转运体和酶的 mRNA 水平，并用 Western blot 法测定 P-gp 的蛋白水平。通过 calcein 测定法在 P388/dx 和 L-MDR1 细胞中评估 P-gp 抑制作用，通过 pheophorbide A 外排评估 BCRP 抑制作用在 MDCKII-BCRP 细胞中。通过在过表达特定 ABC 转运体的 MDCKII 细胞中进行生长抑制测定评估底物特征。
阿特森坦强烈诱导了几种 CYP 和药物转运体（例如，在 50μM 时 CYP3A4 的诱导倍数为 12 倍）。它是一种中等强度的 P-gp 抑制剂（在 P388/dx 细胞中的 IC（50）为 15.1±1.6μM），也是一种较弱的 BCRP 抑制剂（在 MDCKII-BCRP 细胞中的 IC（50）为 59.8±11μM）。BCRP 或 P-gp 过表达细胞对阿特森坦的抗增殖作用略具抗性。
我们的数据提供了对阿特森坦的诱导谱及其与 P-gp 和 BCRP 的相互作用的全面分析。深刻的诱导作用强调了在体内彻底评估其相互作用潜力的必要性。
