LYMPHATIC TARGETING OF ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS NUCLEOSIDES - PHARMACOKINETICS OF 3'-DEOXY-2',3'-DIDEHYDROTHYMIDINE AFTER INTRAVENOUS AND ORAL-ADMINISTRATION OF DIPALMITOYLPHOSPHATIDYL PRODRUG TO MICE

The lymphatic system is a primary target for early antihuman immunodef iciency virus drug therapy. Strategies are currently being sought to e nhance the delivery of nucleoside analogues such as 3'-deoxy-2',3'-did ehydrothymidine (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 mic e. The pharmacokinetics of d4T were characterized following administra tion of a single intravenous or oral dose of 50 mg kg(-1) d4T and an e quimolar dose (214 mg kg(-1)) of DPP-d4T. Concentrations of d4T in ser um and ph nodes were determined by HPLC. Following administration of d 4T, the distribution of d4T into lymph nodes was rapid with maximum co ncentrations 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 conc entrations of d4T in serum and lymph nodes. Approximately 67% of the i ntravenously administered DPP-d4T was biotransformed to parent compoun d. The apparent oral bioavailability of DPP-d4T was low. While the pho spholipid prodrug did not increase d4T concentrations in the lymph nod es, it did provide an extended release of the parent nucleoside, resul ting in sustained concentrations of d4T.