Unraveling the pharmaceutical excipient-drug interactions: The effects of polyethylene glycol copolymers on drug metabolism and transport systems.

Polyethylene glycol (PEG), a versatile and biocompatible polymer, serves as a key pharmaceutical excipient in the development and application of novel clinical drug formulations. It not only illustrates the enhancement of drug stability and bioavailability in conventional formulations, including injections, soft capsules, and drop pills, but it also can modify biomacromolecular drugs and nanodrug delivery systems (NDDS) via PEGylation technology to form PEGylated drugs and PEG copolymer carrier materials. Using PEG copolymer carrier materials in NDDS provides a promising strategy for tumor-targeted drug delivery. However, despite the numerous advantages of PEG copolymers as pharmaceutical excipients in clinical formulations, there is limited attention to their potential to induce pharmaceutical excipient-drug interactions (EDI). In fact, accumulating evidence suggests that PEG copolymers affect the metabolic transport systems of drugs. Therefore, this review summarizes recent research on the effects of commonly used PEG copolymers, including PEG, PEG-polycaprolactone (PEG-PCL), PEG-polylactic acid (PEG-PLA), PEG-poly (lactic-co-glycolic acid) (PEG-PLGA), Pluronic, D-alpha-tocopheryl polyethylene glycol succinate (TPGS), and 1,2-distearoyl-sn-glycero-3-phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG), on drug phase I cytochrome P450 (CYP) and phase II uridine-5'-diphospho-glucuronosyltransferase (UGT) metabolic enzymes, drug transporters, and gut microbiota. This review will provide references for drug design, development, and rational clinical use.