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

Abstract

SummaryHuman immunodeficiency virus appears to be proliferating within the lymphatic system throughout the period of clinical latency. Targeting of anti-HIV compounds to the lymphatic tissue may therefore provide therapeutic benefits. The purpose of this investigation was to determine the distribution of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (AZdU) in lymph nodes in a mouse model after administration of the lipophilic prodrugs dipalmitoylphosphatidyl-azidodeoxythymidine (DPP-AZT) and dipalmitoylphosphatidyl-azidodideoxyuridine (DPPAZdU). 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 180mg kg-1 DPPAZdU (equivalent to 50 mg kg-1 AZdU) orally. Serum, neck, axillary and mesenteric lymph nodes were collected at selected times and AZT and AZdU concentrations were determined by HPLC. The disposition of AZT and AZdU in serum and lymph nodes was significantly altered after intravenous and oral administration of DPP-AZT and oral administration of DPP-AZdU when compared to that after administration of parent nucleoside. Lower peak concentrations of AZT and AZdU were observed in serum and lymph nodes after administration of the phospholipid prodrugs. However, DPP-AZT and DPP-AZdU produced consistently higher concentrations of AZT and AZdU, respectively, Received 11 January, 1995; accepted 21 February, 1995 © 1995 Blackwell Science Ltd 2-3 h after prodrug administration. Half-life values for both nucleosides in serum and lymph nodes were significantly greater after prodrug administration.Greater 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 node exposure to AZT and AZdU in the lymph nodes was greater after administration of prodrug than after administration of parent compound. Thus, DPP-AZT and DPP-AZdU show potential as useful prodrugs for the delivery of AZT and AZdU to the lymphatic system.

Synthesis of Azidothymidine-Bound Curdlan Sulfate with Anti-Human Immunodeficiency Virus Activity in vitro

“…This discovery suggested that targeting of AIDS drug to lymphatic tissue and sustaining a high therapeutic drug concentration in lymphatic tissue may improve therapeutic benefits, especially in the latent period. However, it has been reported that azidothymidine (AZT) administration during an early clinical latent stage did not provide benefits to HIV -infected patients, 3 since AZT fails to be targeted and sustained in lymphatic tissue, 4 • 5 and has serious side effects and drug resistance. 6 Therefore, preparation of an AZT prodrug which may deliver AZT to lymphatic tissue and maintain effective AZT concentration in lymphatic tissue is of importance.…”

Electrospray ionization mass spectrometry of AZT H‐phosphonates conjugated with steroids

“…3′‐Azido‐3′‐deoxythymidine ( 1 , AZT, Zidovudine, Retrovir) was the first chemical agent approved by the Food and Drug Administration (FDA) for the treatment of AIDS 1. However, there were some major problems in its clinical application, such as bone marrow toxicity and suppression, low therapeutic index and low localization in the brain 2,3. In order to improve the therapeutic potential of AZT, a number of prodrugs have been synthesized to deliver AZT in vivo 4.…”

Effects of 6-Chloro-2',3'-Dideoxyguanosine (6-Cl-ddG) in Surface Lymph Nodes of Rhesus Monkeys (Macaca mulatta) Chronically Infected with Simian Immunodeficiency Virus (SIVmac239).

“…Manouilov et al demonstrated that lipophilicity is a key factor for retention of antiretroviral drugs in lymph nodes [14]. The 6-Cl-ddG is a highly lipophilic antiretroviral prodrug [22].…”

“…Manouilov et al demonstrated that lipophilicity is a key element in the targeting of antiretroviral drug to lymph nodes [14]. They showed that, in mice, administrated AZT rapidly disappears from lymph nodes serologically negative for B virus, simian T-cell leukemia virus type I and simian type D retrovirus.…”

“…compared with the lipophilic prodrug of AZT, dipalmitoylphosphatidyl-AZT [14]. The unique structure of 6-Cl-ddG (i.e., the chlorine at portion 6 of 2', 3'-dideoxyguanosine) increases lipophilicity [22], and may promote efficacy of ddG in lymph nodes.…”