       Document 0504
 DOCN  M9630504
 TI    Enhanced oral bioavailability of DDI after administration of 6-Cl-ddP,
       an adenosine deaminase-activated prodrug, to chronically catheterized
       rats.
 DT    9603
 AU    Anderson BD; Morgan ME; Singhal D; Department of Pharmaceutics and
       Pharmaceutical Chemistry,; University of Utah, Salt Lake City 84112,
       USA.
 SO    Pharm Res. 1995 Aug;12(8):1126-33. Unique Identifier : AIDSLINE
       MED/96021486
 AB    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.
 DE    Adenosine Deaminase/*METABOLISM  Administration, Oral  Animal  Antiviral
       Agents/ADMINISTRATION & DOSAGE/BLOOD/*PHARMACOKINETICS  Biological
       Availability  Biotransformation  Catheterization  Chromatography, High
       Pressure Liquid  Didanosine/ADMINISTRATION &
       DOSAGE/BLOOD/*PHARMACOKINETICS  Hepatic Veins  Infusions, Intravenous
       Male  Models, Biological  Prodrugs/ADMINISTRATION &
       DOSAGE/*PHARMACOKINETICS  Purine Nucleosides/ADMINISTRATION &
       DOSAGE/BLOOD/  *PHARMACOKINETICS  Rats  Rats, Sprague-Dawley  Support,
       U.S. Gov't, P.H.S.  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

