Development and in vivo evaluation of an oral drug delivery system for paclitaxel

✍ Scribed by Javed Iqbal; Federica Sarti; Glen Perera; Andreas Bernkop-Schnürch

• Publisher: Elsevier Science
• Year: 2011
• Tongue: English
• Weight: 221 KB
• Volume: 32
• Category: Article
• ISSN: 0142-9612
• DOI: 10.1016/j.biomaterials.2010.09.036

✦ Synopsis

The aim of the present study was to investigate the effect of poly(acrylic acid)-cysteine (PAA-cysteine) exhibiting a molecular mass of 100 and 250 kDa and reduced glutathione (GSH) on the absorption of the P-glycoprotein (P-gp) and cytochrome P450 (CYP450) substrate paclitaxel in vitro and in vivo. In vitro transport studies were performed with Caco-2 monolayers. Furthermore, the delivery system based on PAA-cysteine, GSH and paclitaxel was evaluated in vivo in rats. In vitro, the formulation comprising 0.5% (m/v) PAA-cysteine (100 kDa)/0.5% (m/v) GSH improved the transport of paclitaxel 6.7-fold (P app ¼ 8.7 AE 1.3 Â 10 À6 cm/s) in comparison to paclitaxel itself serving as buffer only control (P app ¼ 1.3 AE 0.4 Â 10 À6 cm/s). Moreover, in the presence of the formulation containing 0.5% (m/v) PAAcysteine (250 kDa)/0.5% (m/v) GSH paclitaxel absorption was even 7.4-fold (P app ¼ 9.7 AE 0.3 Â 10 À6 cm/s) improved in comparison to the buffer only control. In vivo, the oral administration of formulations containing 1 mg of paclitaxel, 1 mg of GSH and 8 mg of PAA-cysteine (100 kDa or 250 kDa) resulted in an improved paclitaxel plasma concentration and bioavailability. The area under the plasma concentrationtime curve (AUC 0e8 ) of paclitaxel was 4.7-fold and 5.7-fold improved in comparison to the oral formulation containing paclitaxel alone, respectively. Moreover, c max was improved by 6.3-fold and even 7.3fold in comparison to the oral formulation containing paclitaxel alone, respectively. Thus, according to the achieved results it is suggested that PAA-cysteine in combination with GSH would be a potentially valuable tool for improving the oral bioavailability of P-gp and CYP450 substrates such as paclitaxel.