Interactions of Oral Molecular Excipients with Breast Cancer Resistance Protein, BCRP.

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 (ABCG2), 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 IC50 values less than 5 µM using 3H-cholecystokinin octapeptide (3H-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 3H-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.

Lack of Interactions Between an Antisense Oligonucleotide with 2'-O-(2-Methoxyethyl) Modifications and Major Drug Transporters.

ISIS 141923 is a model compound of 2'-O-(2-methoxyethyl) (2'-MOE) modified antisense oligonucleotides (ASOs). The purpose of this study is to determine whether ISIS 141923 is a substrate or an inhibitor against a panel of nine major uptake or efflux drug transporters, namely breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transporting polypeptide 1B (OATP1B)1, OATP1B3, and bile salt export pump (BSEP), in vitro. The uptake test system for transporters in the solute carrier (SLC) family (OAT1, OAT3, OCT1, OCT2, OATP1B1, and OATP1B3) was studied in Madin-Darby canine kidney (MDCK)-II cells transfected to express the transporters of interest. BCRP was studied using carcinoma colon-2 (Caco-2) cells with endogenously expressed BCRP. P-gp transporter was studied in MDCK-multi-drug resistance 1 (MDR1) cells, while BSEP was studied using Spodoptera frugiperda 9 (Sf9) membrane vesicles containing human BSEP. The ISIS 141293 concentrations evaluated were 10 and 100 µM for the substrate and inhibition study, respectively. Cellular uptake of ISIS 141923 was analyzed using a high performance liquid chromatography-mass spectrometry method, while concentrations of known substrates (used as positive controls) of each transporters evaluated were determined by radiometric detection. At 10 µM ISIS 141923, there was no significant transporter-mediated uptake of ISIS 141923 (P > 0.05) in the SLC family, and the efflux ratios were not above 2.0 for either BCRP or P-gp. Therefore, no transporter-mediated uptake of ISIS 141923 was observed by any of the nine transporters studied. At 100 µM ISIS 141923, the % inhibition was in the range of -16.0% to 19.0% for the nine transporters evaluated. Therefore, ISIS 141923 is not considered as an inhibitor of the nine transporters studied. Overall, the results from this study suggest that it is unlikely that ISIS 141923 or similar 2'-MOE ASOs would interact with small molecule drugs either as a victim (substrate) or perpetrator (inhibitor) of major transporters in humans. The results from available clinical drug-drug interaction studies conducted with this class of compounds to date are also supportive of this conclusion.