Lymphatic targeting of anti-HIV nucleosides: distribution of 2',3'-dideoxyinosine after intravenous and oral administration of dipalmitoylphosphatidyl prodrug in mice.
In the search for prodrugs of 2',3'-dideoxyinosine (ddI) with potential for improving the delivery of the nucleoside analogue to the lymphatic system, we synthesized dipalmitoylphosphatidyl-2',3'-dideoxyinosine (DPP-ddI) and its pharmacokinetics were investigated in mice. The disposition of ddI in plasma and lymph nodes was examined following intravenous and oral administration of parent nucleoside (100 mg/kg) and DPP-ddI (400 mg/kg, equivalent to 100 mg/kg of ddI). Concentrations of ddI were determined by HPLC. Pharmacokinetic parameters were estimated by area/moment analysis. Intravenous administration of DPP-ddI resulted in a pattern of lower peak concentrations of ddI and more sustained exposure of parent nucleoside in plasma and lymph nodes compared to administration of the parent nucleoside. Both ddI and DPP-ddI yielded similar AUC values in lymph nodes. Oral administration of the prodrug resulted in lower concentrations and AUC values of ddI in plasma and lymph nodes when compared to administration of the parent nucleoside. The bioavailability of ddI following ddI and DPP-ddI administration was 15 and 8%, respectively. The results of the present study demonstrate that DPP-ddI administered intravenously shows potential for targeting and sustaining level of ddI in the nodular lymphatic tissues.
Manouilov
K K
KK
College of Pharmacy, University of Georgia, Athens 30602, USA.
Xu
Z S
ZS
Boudinot
F D
FD
Schinazi
R F
RF
Chu
C K
CK
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D016049:Didanosine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D007275:Injections, Intravenous; D008208:Lymphatic System / Q000378:metabolism*; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D019380:Anti-HIV Agents; D011355:Prodrugs; C107380:dipalmitoylphosphatidyl-2',3'-dideoxyinosine; D016049:Didanosine