Synthesis and evaluation of 5' alkyl ester prodrugs of zidovudine for directed lymphatic delivery

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Abstract

The butanoic, lauric and oleic acid ester prodrugs of the anti-AIDS drug zidovudine (AZT) have been synthesised and assessed for their ability to promote the transport of AZT through the intestinal lymph (a major reservoir for the human immunodeficiency virus (HIV)). The octanol/water partition co-efficient and triglyceride solubility of the AZT prodrugs increased with increasing chain length of the alkyl pro-moiety, and the observed values were consistent with that required for potential intestinal lymphatic transport after oral administration. The intestinal lymphatic transport of AZT and the ester prodrugs was assessed after intraduodenal administration as a micellar lipid solution in an anesthetised rat model. Systemic blood was also sampled in order to estimate the overall extent of absorption. The lymphatic transport of AZT was similar when administered as either AZT alone or the lipophilic ester prodrugs, where the amount of AZT collected in fistulated mesenteric lymph was approximately 0.1-0.2% of the administered dose (15 mg/kg AZT). The extent of absorption of AZT, estimated from the area under the plasma concentration time profiles of AZT, when dosed as either parent compound or the lipophilic esters, was essentially complete. These data suggest that rapid bioconversion of the ester prodrugs to AZT in either the intestinal lumen or the enterocyte limits exploitation of this approach as a means of enhancing the selective lymphatic delivery of AZT.

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Bibby, D. C., Charman, W. N., Charman, S. A., Iskander, M. N., & Porter, C. J. H. (1996). Synthesis and evaluation of 5’ alkyl ester prodrugs of zidovudine for directed lymphatic delivery. International Journal of Pharmaceutics, 144(1), 61–70. https://doi.org/10.1016/S0378-5173(96)04720-5

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