Intestinal permeation of zidovudine and zidovudine prodrugs measured in rat intestinal segments

QUEVEDO, M.A.; BRIÑÓN, M.C.

Buenos Aires, Argentina

Simposio; International Symposium on Drug Transport and Metabolism; 2009

Sociedad Argentina de Farmacología Experimental

Zidovudine (AZT) was the first approved to treat AIDS syndrome, and still is part of the Highly Active Antiretroviral Therapy (HAART) regimen.1 Although the clinical efficacy has being vastly demonstrated, its oral absorption and biodistribution properties still need to be fully understood and optimized.2 As part of our studies dealing with the design and development of novel prodrugs of AZT with potential application to HAART, this work deals with the evaluation of intestinal permeation properties of AZT and two novel prodrugs of AZT,3,4 by applying the intestinal gut sac technique. With this aim, the corresponding apparent permeability coefficients (Papp) were determined in the basal-to-apical and apical-to-basal direction, analyzing different small intestine portions and drug concentrations. Our findings demonstrated that AZT exhibited no difference in its apical-to-basal permeability in proximal segments of small intestine at all concentrations assayed, while a lower permeability was found in distal ileum at higher concentrations. Also a significant decrease in the amount of drug transported was found when the time of exposure of the tissue to the drug was prolonged. The decrease in AZT transport in the apical-to-basal direction in distal ileum was not observed in presence of verapamil, thus evidencing a P-gp mediated mechanism. When the permeability in the basal-to-apical direction was evaluated, an increase in the amount of drug transported with respect to time at high drug concentrations was observed, clearly suggesting an efflux pattern which may reduce AZT bioavailability. From the above commented results, a rapid P-gp activity up-regulation is proposed. Two novel prodrugs of AZT (AZT-Iso and AZT-Ac),3,4 obtained and currently under development in our research group, were evaluated by means of this assay. AZT-Iso exhibited an enhanced lipophilicity respect to that of AZT, but was completely hydrolyzed during its permeation through the enterocyte, with identical permeation patterns to those determined for AZT. On the other hand, AZT-Ac, a highly hydrophilic prodrug of zidovudine,5 was able to permeate through the intestinal tissue without significant enzymatic or chemical hydrolysis. When AZT-Ac apical-to-basal transport was evaluated, lower Papp values were obtained compared to those of AZT, but remarkably no decrease in the amount of permeated drug was observed as time of exposure of the intestinal tissue to this compound increased, suggesting that up-regulation of P-gp may not be present. In contrast to what was observed for AZT, a significant enhancement in AZT-Ac permeability was observed as the drug concentration increased in the mucosal solution. Considering the results presented, the role of P-gp in AZT intestinal efflux needs to be reconsidered, addressing also the dynamic nature of this transporter expression and regulation. Also, the elucidation of the molecular basis of P-gp substrate specificity may be shade some lights for the development of new prodrugs of AZT with enhanced bioavalabilities and biodistribution.