LYMPHATIC TARGETING OF ANTI-HIV NUCLEOSIDES - DISTRIBUTION OF 3'-AZIDO-3'-DEOXYTHYMIDINE (AZT) AND 3'-AZIDO-2',3'-DIDEOXYURIDINE (AZDU) AFTER ADMINISTRATION OF DIPALMITOYLPHOSPHATIDYL PRODRUGS TO MICE

Human immunodeficiency virus appears to be proliferating within the ly mphatic system throughout the period of clinical latency. Targeting of anti-HIV compounds to the lymphatic tissue may therefore provide ther apeutic benefits. The purpose of this investigation was to determine t he distribution of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3' -dideoxyuridine (AZdU) in lymph nodes in a mouse model after administr ation of the lipophilic prodrugs dipalmitoylphosphatidyl-azidodeoxythy midine (DPP-AZT) and dipalmitoylphosphatidyl-azidodideoxyuridine (DPPA ZdU). Mice received 50 mg kg(-1) of parent nucleoside and 164 mg kg(-1 ) of DPP-AZT (equivalent to 50 mg kg(-1) AZT) intravenously or orally and 180 mg kg(-1) DPPAZdU (equivalent to 50 mg kg(-1) AZdU) orally. Se rum, neck, axillary and mesenteric lymph nodes were collected at selec ted times and AZT and AZdU concentrations were determined by HPLC. The disposition of AZT and AZdU in serum and lymph nodes was significantl y altered after intravenous and oral administration of DPP-AZT and ora l administration of DPP-AZdU when compared to that after administratio n of parent nucleoside. Lower peak concentrations of AZT and AZdU were observed in serum and lymph nodes after administration of the phospho lipid prodrugs. However, DPP-AZT and DPP-AZdU produced consistently hi gher concentrations of AZT and AZdU, respectively, 2-3 h after prodrug administration. Half-life values for both nucleosides in serum and ly mph nodes were significantly greater after prodrug administration. Gre ater AUC values for nucleosides were noted in neck (AZT and AZdU) and mesenteric (AZT) lymph nodes after administration of prodrugs compared with values obtained for parent drugs. Furthermore, relative lymph no de exposure to AZT and AZdU in the lymph nodes was greater after admin istration of prodrug than after administration of parent compound. Thu s, DPP-AZT and DPP-AZdU show potential as useful prodrugs for the deli very of AZT and AZdU to the lymphatic system.