The pharmaceutical excipient PEG400 affect the absorption of baicalein in Caco‐2 monolayer model by interacting with UDP‐glucuronosyltransferases and efflux transport proteins

Abstract

The bioavailability of drugs is often related to intestinal metabolism and transport mechanisms. In previous studies, pharmaceutical excipients were recognized as inert substances in clinical safety evaluations. However, a large number of studies have shown that pharmaceutical excipients regulate the metabolism and transport of drugs in the body and improve the bioavailability. The pharmaceutical excipient polyethylene glycol 400 (PEG400) as a good solubilizer and surfactant has the potential to improve the bioavailability of drugs. The combined action of UDP‐glucuronosyltransferases (UGTs) and efflux transport proteins is responsible for the intestinal disposition and poor bioavailability of baicalein. Our aim is to study the effect of PEG400 on the absorption of baicalein on the Caco‐2 monolayer, and confirm the interaction of PEG400 with UGTs (UGT1A8 and UGT1A9) and efflux transports. We initially found that baicalein in the Caco‐2 monolayer would be metabolized into glucuronide conjugates BG and B6G under the action of UGT1A8 and UGT1A9 on the endoplasmic reticulum membrane, and then mainly excreted to different sides by acting of MRP and BCRP. The addition of PEG400 significantly accelerated the metabolism of B in Caco‐2 cells and increased the penetration of BG and B6G. Furthermore, PEG400 also significantly decreased the efflux ratio of BG and B6G, which was the evidence of the interaction with the efflux transporters. In the in vitro intestinal microsome regeneration system, low concentration PEG400 decreased the Km value of UGT1A8 and UGT1A9 (key enzymes that mediate the production of BG and B6G); high concentration PEG400 enhanced the Vmax value of UGT1A8 and UGT1A9. In conclusion, our results determined that PEG400 interacted with some UGTs and efflux transporters, which were the main factors affecting the absorption of baicalein.

Study on the Effect of Pharmaceutical Excipient PEG400 on the Pharmacokinetics of Baicalin in Cells Based on MRP2, MRP3, and BCRP Efflux Transporters

“…It is suggested that PEG400 may activate the related phase II metabolic enzymes. A previous study by the group showed that PEG400 had a significant promoting effect on UGT1A8 and UGT1A9 [ 39 , 40 ].…”

Detrimental Impacts of Pharmaceutical Excipient PEG400 on Gut Microbiota and Metabolome in Healthy Mice

“…Studies have shown that PEG400 alters the systemic exposure of drugs through multiple pathways, such as drug-metabolizing enzymes and transporter functions, affecting cell membrane microenvironments and reversibly opening tight junctions [5][6][7][8][9]. Our previous study also showed that PEG400 could increase the blood concentration and tissue distribution of baicalin by inducing the activities of UGT1A8 and UGT1A9 [10][11][12]. Furthermore, we found that the long-term application of PEG400 as the matrix for TCM soft capsules can cause diarrhea and weight loss in animals, which reminds us to pay attention to the potential impact on healthy bodies.…”