SYNTHESIS AND EVALUATION OF 5'-ALKYL ESTER PRODRUGS OF ZIDOVUDINE FORDIRECTED LYMPHATIC DELIVERY

The butanoic, lauric and oleic acid ester prodrugs of the anti-AIDS dr ug zidovudine (AZT) have been synthesised and assessed for their abili ty to promote the transport of AZT through the intestinal lymph (a maj or reservoir for the human immunodeficiency virus (HIV)). The octanol/ water partition co-efficient and triglyceride solubility of the AZT pr odrugs increased with increasing chain length of the alkyl pro-moiety, and the observed values were consistent with that required for potent ial intestinal lymphatic transport after oral administration. The inte stinal 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 es timate the overall extent of absorption. The lymphatic transport of AZ T was similar when administered as either AZT alone or the lipophilic ester prodrugs, where the amount of AZT collected in fistulated mesent eric 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 unde r the plasma concentration time profiles of AZT, when dosed as either parent compound or the lipophilic esters, was essentially complete. Th ese 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 deliv ery of AZT.