Speaker
Description
Polyethylene glycol 400 (PEG 400), a pharmaceutical excipient approved by both the U.S. Food and Drug Administration and the Chinese Pharmacopoeia, is widely employed in clinical formulations due to its favorable biocompatibility and hydrophilicity. Therefore, whether PEG induces excipient-drug interactions and alters the in vivo disposition of active pharmaceutical ingredients has become a clinical drug safety concern. In recent years, we conducted a comprehensive investigation employing spatial mass spectrometry imaging, gene knockout, and Western blot analyses to evaluate the effects of PEG 400 on the metabolism (via uridine-5′-diphospho-glucuronosyltransferase (UGT)1A8, UGT1A9, and UGT2B7) and transport (via breast cancer resistance protein (BCRP), multidrug resistance-related protein (MRP)2, and MRP3) of the natural compound baicalin (BG) and the clinical drug mycophenolic acid (MPA) at molecular, cellular, and whole-animal levels. Pharmacokinetic and spatial mass spectrometry imaging studies demonstrated that oral administration of PEG 400 significantly increased the area under the plasma concentration-time curve of both BG and MPA, as well as the tissue distribution of MPA in the heart, liver, spleen, and kidneys of rats. Molecular docking analyses indicated that PEG 400 can bind to UGT1A8, UGT1A9, BCRP, MRP2, and MRP3. Additionally, PEG 400 also upregulated the activity, mRNA expression, and protein levels of UGT1A8, UGT1A9, UGT2B7, and MRP3, while downregulating those of BCRP and MRP2. In conclusion, our study demonstrates that PEG 400 alters the pharmacokinetics and tissue distribution of both BG and MPA by modulating the activity and expression of drug-metabolizing enzymes (UGT1A8, UGT1A9, and UGT2B7) and transporters (BCRP, MRP2, and MRP3) .
