Departments of Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb Research and Development, Princeton, NJ, 08543, USA.
Nonclinical Disposition & Bioanalysis, Bristol Myers Squibb Research and Development, Princeton, NJ, 08543, USA.
Pharm Res. 2023 Nov;40(11):2567-2584. doi: 10.1007/s11095-023-03563-4. Epub 2023 Jul 31.
The differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition.
We assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP.
ECD is a potent inhibitor with a high degree of selectivity in inhibiting human P-gp (hP-gp) over human BCRP (hBCRP) (ICs of 0.0058 ± 0.0006 vs. > 10 µM, respectively). In contrast, ECD is a potent inhibitor of rat and cynomolgus monkey BCRP (IC ranged from 0.059 to 0.18 µM). While the AUC of IV paclitaxel (PTX) was significantly increased by elacridar (ELD) (P < 0.05) but not ECD in rats (15 mg/kg; PO) (2.55- vs. 0.93-fold), that of PO PTX was significantly elevated to a similar extent between the inhibitors (39.5- vs. 33.5-fold). Similarly, the AUC of PO sulfasalazine (SFZ) was dramatically increased by ELD and ECD (16.6- vs. 3.04-fold) although that of IV SFZ was not significantly affected by ELD and ECD in rats (1.18- vs. 1.06-fold). Finally, a comparable ECD-induced increase of the AUC of PO talinolol in cynomolgus monkeys was observed compared with ELD (2.14- vs. 2.12-fold).
ECD may allow an in-depth appraisal of the role of intestinal efflux transporter(s) in drug disposition in animals and humans through local intestinal drug interactions.
肠道和全身（肝和肾）P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）在药物处置中的作用差异难以确定。因此，我们将恩赛奎达（ECD）鉴定为一种肠道 P-gp 和 BCRP 特异性抑制剂，以评估其在药物处置中的作用。
我们评估了 ECD 对人和动物 P-gp 和 BCRP 的体外和体内抑制潜力。
ECD 是一种强效抑制剂，对人 P-gp（hP-gp）的抑制具有高度选择性，而对人 BCRP（hBCRP）的抑制作用较弱（IC 分别为 0.0058 ± 0.0006 和 > 10 μM）。相比之下，ECD 是大鼠和食蟹猴 BCRP 的强效抑制剂（IC 范围为 0.059 至 0.18 μM）。在大鼠（15mg/kg；PO）中，伊立替康（PTX）的 AUC 显著增加（P < 0.05），但不是 ECD（2.55- 与 0.93 倍），而 PO PTX 的 AUC 与抑制剂之间的升高程度相似（39.5- 与 33.5 倍）。同样，PO 柳氮磺胺吡啶（SFZ）的 AUC 也显著增加，无论是 ELD 还是 ECD（16.6- 与 3.04 倍），尽管大鼠中 IV SFZ 不受 ELD 和 ECD 的显著影响（1.18- 与 1.06 倍）。最后，在食蟹猴中观察到 ECD 诱导的 PO 他林洛尔 AUC 增加与 ELD 相当（2.14- 与 2.12 倍）。
ECD 可能通过局部肠道药物相互作用，允许深入评估肠道外排转运体在动物和人体中药物处置中的作用。
