LYMPHATIC DISTRIBUTION OF 3'-AZIDO-3'-DEOXYTHYMIDINE AND 3'-AZIDO-2',3'-DIDEOXYURIDINE IN MICE

Recently, it was shown that human immunodeficiency virus (HIV)-infecte d cells preferentially locate in lymphoid tissue early in the course o f infection. Therefore, it is important to characterize the dispositio n of the anti-HIV agents, 3'-azido-3'-deoxythymidine (AZT) and 3'-azid o-2',3'-dideoxyuridine (AZdU), in the lymphatic system. The dispositio n of AZT and AZdU in serum and neck, axillary, and mesenteric lymph no des was studied in mice after intravenous, oral, and intraperitoneal a dministrations of 50 mg/kg doses. Samples were collected at 0.08, 0.5, 1, 2, 3, 4, and 6 hr after dosing and nucleoside concentrations were determined by HPLC. Pharmacokinetic parameters were estimated using no ncompartmental analysis. Maximum concentration, half-life, and area un der the serum concentration vs. time curve (AUG) obtained from the ser um concentration data were similar for both compounds after intravenou s and intraperitoneal administrations; however, a difference in oral b ioavailability for AZT and AZdU (49% and 76%, respectively) was noted. Patterns of regional distribution in lymph nodes were similar for bot h drugs; however, the accumulation of AZdU in the various lymph nodes, according to AUC values, was 3-76% greater than that for AZT. The rel ative exposure (r(e) = AUC(lymph)/AUC(serum)) of both nucleosides exhi bited a dependence on route of administration. Intravenous and oral ad ministrations resulted in a greater distribution of nucleoside into ax illary lymph nodes, compared with neck and mesenteric lymph nodes. Fol lowing intraperitoneal administration, however, distribution was simil ar in all three regions. AZT and AZdU distribute into the lymphatic sy stem; however, AZdU accumulation was greater than that of AZT. Regiona l differences in nucleoside lymphatic distribution, as well as a depen dence on route of administration, were observed.