In vitro and in vivo pharmacokinetic characterization of two novel prodrugs of zidovudine

This work deals with the in vitro and in vivo pharmacokinetic characterization of 3′-azido-2′,3′-dideoxy-5′-O-oxalatoylthymidine (AZT-Ac) and 3′-azido-2′,3′-dideoxy-5′-O-isonicotinoyl-thymidine (AZT-Iso), two novel prodrugs of the anti-HIV agent zidovudine [3′-azido-2′,3′-dideoxythymidine (AZT)]. AZT, AZT-Ac and AZT-Iso intestinal permeation properties and plasma concentration profiles in rats after intravenous administration were studied. Using the everted gut sac intestinal permeation assay, it was observed that AZT was subjected to saturable transport mechanisms in the jejunum and the proximal ileum, while no saturation was found in the distal ileum. AZT-Ac was able to permeate the intestinal segment at a lower rate than AZT but resisting enzymatic hydrolysis, while no evidence of saturation was found. On the other hand, AZT-Iso was completely hydrolyzed in the intestinal tissue, with AZT being found in the permeated samples. In vivo studies demonstrated that AZT plasma half-life (t1/2) is extended after administration of AZT-Ac compared to AZT (2.16 and 0.96 h, respectively), while after administering AZT-Iso the t1/2 of the regenerated AZT was shorter (0.38 h). A relationship is proposed between these observed in vivo pharmacokinetic features and previous studies of protein-binding properties, concluding that AZT-Ac is a very promising prodrug of AZT in the search for more effective and safer anti-HIV agents.