Intestinal permeation of new zidovudine prodrugs designed to optimize biopharmaceutical properties

SCHENFELD, E.M.; QUEVEDO, M.A.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Zidovudine (AZT) is an anti-VIH drug widely used to treat AIDS. Despite its clinical efficacy, AZT presents variable and low bioavailability which in turn result in severe adverse effects. The present work reports the intestinal permeation studies using a ex vivo intestinal gut sac technique of four new AZT derivates: AZT-Suc-Fen-O-met (1), AZT-Suc-Iso-O-met (2), AZT-Glu-Fen-O-met (3), AZT-Adi-Fen-O-met (4), designed to enhance the bioavailability and protein binding properties of AZT.In a first stage, a bioanalytical method was developed and validated to quantify AZT and the studied prodrugs prodrugs in TC199, with the corresponding chemical stability being also evaluated. In a next stage, the intestinal permeation of AZT and 1-4 was evaluated in proximal jejunum, at two concentrations (0.45 x 10-5 M and 1 x 10-5 M) in the presence and absence of the Pgp inhibitor Verapamil. The results showed that the magnitudes of the apparent permability (Papp) was 3<2<1<4. The Papp of 4 is not statistically different to that of AZT (p >0.05), while the rest of the derivativves exhibited a less overall permeability compared to AZT AZT (p< 0.05). In particular, compound 1 permeated by passive diffusion and was not subjected to Pgp mediated efflux, while 2 permeated by passive diffusion and was subjected to Pgp efflux. Respect to 3, this derivative presented a low permeability and a high efflux, while prodrug 4 presented the highest intrinsic permeability among the studied compounds and was also able regenerate AZT by metabolism inside the enterocyte.In conclusion, in this study we report four new AZT derivates that exhibiting different absorption mechanisms. In particular, the prodrug 4 presented a similar overall permeability to that observed for to AZT without being subject to Pgp efflux. These findings constitutes a significant advantage for the design of new prodrugs able to optimize AZT biopharmaceutical properties.