Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California 94158, United States.
Department of Pharmaceutical Chemistry & QB3 Institute, University of California, San Francisco, California 94158, United States.
Mol Pharm. 2020 Mar 2;17(3):748-756. doi: 10.1021/acs.molpharmaceut.9b00658. Epub 2020 Feb 10.
Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC values less than 5 μM using H-cholecystokinin octapeptide (H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.
基于机制理解的辅料选择可能会改进仿制药产品的配方开发策略，并有可能加速其批准。我们的研究旨在调查口服 FDA 批准的药物产品中存在的分子辅料对肠外排转运蛋白 BCRP（）的影响，BCRP 在药物吸收中起着关键作用，可能对药物安全性和疗效有影响。我们在分离的膜囊泡中测定了 136 种口服分子辅料与 BCRP 的相互作用，并使用 H-胆囊收缩素八肽（H-CCK8）确定了 26 种 BCRP 抑制剂的 IC 值小于 5 μM。这些 BCRP 抑制剂属于三种辅料功能类别：染料、表面活性剂和调味剂。与非抑制剂相比，BCRP 抑制剂具有显著更高的分子量和 SLogP 值。在类似浓度下，还在过表达 BCRP 的 HEK293 细胞中评估了在膜囊泡中鉴定出的辅料的抑制作用。在囊泡中鉴定出的 26 种 BCRP 抑制剂中，只有 1 种抑制剂对 BCRP 介导的 H-氧嘌呤醇摄取的抑制作用超过 50%，这与 BCRP 抑制取决于抑制剂的跨膜或细胞内可用性的观点一致。总的来说，这项研究的结果为具有 BCRP 底物的活性药物成分的药物产品开发过程中的辅料选择提供了新信息。
