High-dose etoposide formulations do not saturate intestinal P-glycoprotein: Development, stability, and pharmacokinetics in Sprague-Dawley rats

It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic (R) F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide's solubility approximately 100 times (16 mg mL(-1)) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC0-8 of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg(-1)), AUC0-8 and Cmax were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg(-1). A single oral dose of 20 mg kg(-1) zosuquidar followed by 20 mg kg(-1) oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide.