No abstract

The lymphatic system is a primary target for early anti-human immunodeficiency virus drug therapy. Strategies are currently being sought to enhance the delivery of nucleoside analogues such as 3′-deoxy-2′,3′-didehydrothymidine (stavudine; d4T) toward the lymph and lymph nodes. The purpose of this study was to synthesize dipalmitoylphosphatidyl-d4T (DPP-d4T) as a lipophilic prodrug of d4T and to evaluate the lymphatic distribution of d4T following administration of d4T and DPP-d4T to mice. The pharmacokinetics of d4T were characterized following administration of a single intravenous or oral dose of 50 mg kg−1 d4T and an equimolar dose (214 mg kg−1) of DPP-d4T. Concentrations of d4T in serum and lymph nodes were determined by HPLC. Following administration of d4T, the distribution of d4T into lymph nodes was rapid with maximum concentrations observed within 5 min after dosing. The AUC and half-life values of d4T in three groups of lymph nodes were similar to those in serum. Administration of DPP-d4T resulted in significantly lower concentrations of d4T in serum and lymph nodes. Approximately 67% of the intravenously administered DPP-d4T was biotransformed to parent compound. The apparent oral bioavailability of DPP-d4T was low. While the phospholipid prodrug did not increase d4T concentrations in the lymph nodes, it did provide an extended release of the parent nucleoside, resulting in sustained concentrations of d4T.

4-Azido-2-pyrimidinone Nucleosides and Related Chemistry.-With a view to develop prodrugs for antitumor and antiviral agents, compound (IV) is synthesized and its chemical stability is studied at various pHs by UV spectroscopy. Under acidic conditions (IV) remains stable, but even at pH 7 an 2',6-anhydro bond formation is observed leading to cyclized product (V). The fluoro analogue (VI) shows another reactivity. It is stable at pH 7.4 and undergoes at higher pHs in the presence of NH 4 OH an amine addition yielding product (VII). This demonstrates, that the presence of 2'-OH in the arabino configuration in compound (IV) is necessary for the 2',6-linkage. -(KOTRA, L. P.; WANG, P.; BARTLETT, M. G.; SHANMUGANATHAN, K.; XU, Z.; CAVALCANTI, S.; NEWTON, M. G.; CHU, C. K.; J.

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