Nielsen Rasmus Blaaholm, Holm René, Pijpers Ils, Snoeys Jan, Nielsen Ulla Gro, Nielsen Carsten Uhd
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Drug Product Development, Janssen R&D, Johnson & Johnson, Turnhoutseweg 30, BE-2340 Beerse, Belgium.
Int J Pharm X. 2021 Jul 7;3:100089. doi: 10.1016/j.ijpx.2021.100089. eCollection 2021 Dec.
P-glycoprotein inhibitors, like zosuquidar, have widely been used to study the role of P-glycoprotein in oral absorption. Still, systematic studies on the inhibitor dose-response relationship on intestinal drug permeation are lacking. In the present study, we investigated the effect of 0.79 nM-2.5 μM zosuquidar on etoposide permeability across Caco-2 cell monolayers. We also investigated etoposide pharmacokinetics after oral or IV administration to Sprague Dawley rats with co-administration of 0.063-63 mg/kg zosuquidar, as well as the pharmacokinetics of zosuquidar itself. Oral zosuquidar bioavailability was 2.6-4.2%, while oral etoposide bioavailability was 5.5 ± 0.9%, which increased with increasing zosuquidar doses to 35 ± 5%. The intestinal zosuquidar concentration required to induce a half-maximal increase in bioavailability was estimated to 180 μM. In contrast, the IC of zosuquidar on etoposide permeability was only 5-10 nM, and a substantial discrepancy of at least four orders of magnitude was thereby identified. Overall, the present study provides valuable insights for future formulation development that applies fixed dose combinations of P-glycoprotein inhibitors to increase the absorption of poorly permeable P-glycoprotein substrate drugs.
P-糖蛋白抑制剂，如唑磺达，已被广泛用于研究P-糖蛋白在口服吸收中的作用。然而，关于抑制剂剂量-反应关系对肠道药物渗透影响的系统性研究仍很缺乏。在本研究中，我们研究了0.79 nM至2.5 μM唑磺达对依托泊苷透过Caco-2细胞单层通透性的影响。我们还研究了在0.063至63 mg/kg唑磺达共同给药的情况下，将依托泊苷口服或静脉注射给Sprague Dawley大鼠后的药代动力学，以及唑磺达本身的药代动力学。口服唑磺达的生物利用度为2.6%至4.2%，而口服依托泊苷的生物利用度为5.5±0.9%，随着唑磺达剂量增加至35±5%。诱导生物利用度增加至最大值一半所需的肠道唑磺达浓度估计为180 μM。相比之下，唑磺达对依托泊苷通透性的半数抑制浓度仅为5至10 nM，由此确定了至少四个数量级的显著差异。总体而言，本研究为未来制剂开发提供了有价值的见解，即应用P-糖蛋白抑制剂的固定剂量组合来增加低渗透性P-糖蛋白底物药物的吸收。
