Effects of poly(ethylene glycol) on efflux transporter activity in Caco-2 cell monolayers

Poly(ethylene glycol) (PEG) is an excipient commonly used in pharmaceutical formulations to increase the aqueous solubility of drugs intended for oral administration. High concentrations of PEG are often used to solubilize drug candidates for in vitro experiments in cell culture (e.g., Caco-2 cell permeability studies) and/or for in vivo pharmacokinetic and safety studies in animals. Although PEG is often deemed safe in these studies based on gross morphological studies, changes on a molecular level may be overlooked. The purpose of this study was to determine the possible effects of PEG on efflux transporter activity in Caco-2 cell monolayers, an in vitro model of the intestinal mucosa. In these studies, relatively high, yet clinically achievable, concentrations of PEG-300 did not significantly change the passive paracellular or transcellular permeation of model solutes across Caco-2 cell monolayers. More importantly, PEG-300 inhibited efflux transporter activity in Caco-2 cell monolayers, which is probably mediated by P-gp and/or MRP. Such PEG-induced inhibition of efflux transporter activity is most likely caused by changes in the microenvironment of the Caco-2 cell membranes, which perturbs the ability of these transporters to efflux substrates such as taxol and doxorubicin.