Co-release of paclitaxel and encequidar from amorphous solid dispersions increase oral paclitaxel bioavailability in rats.

The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing the intestinal paclitaxel levels through apparent solubility enhancement and controlling thesimultaneous release of both paclitaxel and the P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase the oral bioavailability of paclitaxel. ASDs of paclitaxel and encequidar in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), and hydroxypropylmethylcellulose 4 K (HPMC-4K) were hence prepared by freeze-drying. In vitro dissolution studies showed that both compounds were released fastest from PVP-K30, then from HPMC-5, and slowest from HPMC-4K ASDs. The dissolution of paclitaxel from all polymers resulted in stable concentration levels above the apparent solubility. The pharmacokinetics of paclitaxel after oral administration to male Sprague-Dawley rats was investigated with or without 1 mg/kg encequidar, as amorphous solids or polymer-based ASDs. The bioavailability of paclitaxel increased 3- to 4-fold when administered as polymer-based ASDs relative to solid amorphous paclitaxel. However, when amorphous paclitaxel was co-administered with encequidar, either as an amorphous powder or as a polymer-based ASD, the bioavailability increased 2- to 4-fold, respectively. Interestingly, a noticeable increase in paclitaxel bioavailability of 24-fold was observed when paclitaxel and encequidar were co-administered as HPMC-5-based ASDs. We, therefore, suggest that controlling the dissolution rate of paclitaxel and encequidar in order to obtain simultaneous and timed release from polymer-based ASDs is a strategy to increase oral paclitaxel bioavailability.

Investigations of potential non-amino acid SNAT2 inhibitors.

The sodium-coupled neutral amino acid transporter 2 (SNAT2, SLC38A2) has been implicated in cancer for its ability to supply cancer cells with glutamine and sarcosine. A recent high-throughput screen published by Gauthier-Coles et al. identified the non-amino acid 3-(N-methyl (4-methylphenyl)sulfonamido)-N-(2-trifluoromethylbenzyl)thiophene-2-carboxamide (MMTC or 57E) as a potent and selective SNAT2 inhibitor. Here we have investigated the ability of MMTC and four other compounds selected from the screen by Gauthier-Coles et al. to decrease 3H-Gly uptake in hyperosmotically treated human prostate cancer PC-3 cells. In these cells, SNAT2 is highly upregulated when the cells are hyperosmotically stressed for 24 h and is the primary contributor to glycine uptake. The five compounds were investigated at concentrations of 1-50 µM based on their equilibrium solubility. At 37°C the equilibrium solubility in HEPES buffered HBSS at pH 7.4 was measured to be 24.9 (53B), 56.1 (54F), 13.3 (55B), and 27.5 (57B) µM, respectively. The equilibrium solubility of MMTC was below the detection limit of the HPLC-UV method, thus less than 1.8 µM. However, a kinetic solubility of approximately 2.5-10 µM could be achieved during the course of the uptake study. In contrast to the previous publication, MMTC showed no inhibition of SNAT2-mediated 3H-Gly uptake in PC-3 cells at a concentration of 1 or 5 µM, despite a published IC50 of 0.8 µM. Similarly, 53B, 55B, and 57B showed no inhibition at soluble conditions, whereas 54F showed approximately 20% inhibition at 50 µM. In our experimental setup, the investigated compounds showed limited potential as SNAT2 inhibitors.