Enhanced oral bioavailability of DDI after administration of 6-Cl-ddP, an adenosine deaminase-activated prodrug, to chronically catheterized rats.

PURPOSE: 6-Cl-2',3'-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue. To examine the feasibility of administering this drug orally, the oral and hepatic portal bioavailabilities of 6-Cl-ddP were determined. In addition, the oral and portal bioavailabilities of ddI after administration of the prodrug were compared to those from administration of ddI itself.
METHODS: Pharmacokinetic and bioavailability studies were conducted in fully conscious, chronically catheterized rats in a randomized crossover design. Plasma ddI and 6-Cl-ddP concentration-time profiles were determined by HPLC.
RESULTS: 6-Cl-ddP has poor apparent oral bioavailability (7% +/- 3%, n = 3) but high bioavailability after portal administration (97% +/- 11%), suggesting either poor absorption or extensive gut wall metabolism. The appearance of > 50% of the dose as ddI in the systemic circulation after an oral dose of 6-Cl-ddP rules out poor absorption of the prodrug, and confirms expectations of high ADA activity in the gastrointestinal tract. Gastric administration of 6-Cl-ddP resulted in a > 10-fold increase in the oral bioavailability of ddI, from 3-7% to > 50%, and a significant decrease in the variability in apparent bioavailability.
CONCLUSIONS: These data indicate that lipophilic adenosine deaminase activated prodrugs of dideoxypurine nucleosides may have limited utility for improving CNS delivery after oral administration but may be useful in enhancing the oral bioavailability of highly polar and therefore poorly absorbed dideoxynucleosides.