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Enhanced oral bioavailability of 2'- beta-fluoro-2',3'-dideoxyadenosine (F-ddA) through local inhibition of intestinal adenosine deaminase.

AbstractPURPOSE:
Intestinal enzyme inhibition may be an effective tool to increase the oral bioavailability of compounds that undergo first-pass intestinal metabolism. However, systemic enzyme inhibition may be undesirable and therefore should be minimized. 2-Beta-fluoro-2',3'-dideoxyadenosine (F-ddA) is an adenosine deaminase (ADA) activated prodrug of 2-beta-fluoro-2',3'-dideoxyinosine (F-ddI) with enhanced delivery to the central nervous system (CNS) that has been tested clinically for the treatment of AIDS. Unfortunately, intestinally localized ADA constitutes a formidable enzymatic barrier to the oral absorption of F-ddA. This study explores various factors involved in inhibitor selection and dosage regimen design to achieve local ADA inhibition with minimal systemic inhibition.
METHODS:
In situ intestinal perfusions with mesenteric vein cannulation were performed in the rat ileum to determine the lumenal disappearance and venous blood appearance of F-ddA and F-ddI. Coperfusions with the ADA inhibitor erythro9-(2-hydroxy-3-nonyl)adenine [(+)-EHNA] over a range of concentrations were used to monitor inhibitor effects on F-ddA absorption and metabolism.
RESULTS:
High concentrations of EHNA in coperfusions with F-ddA completely inhibited intestinal ADA, increasing the permeability coefficient of F-ddA by nearly threefold but producing high systemic inhibition of ADA. Mathematical models were utilized to show that in full-length intestinal perfusions an optimal log mean lumenal EHNA perfusate concentration of 0.5 microg/ml could achieve an intestinal bioavailability of 80% with <20% systemic inhibition.
CONCLUSIONS:
Optimizing local enzyme inhibition may require careful selection of a suitable inhibitor, the dose of the inhibitor, and the inhibitor vs. drug absorption profiles.
AuthorsR T DeGraw, B D Anderson
JournalPharmaceutical research (Pharm Res) Vol. 18 Issue 9 Pg. 1270-6 (Sep 2001) ISSN: 0724-8741 [Print] United States
PMID11683239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adenosine Deaminase Inhibitors
  • Anti-HIV Agents
  • Enzyme Inhibitors
  • lodenosine
  • Dideoxyadenosine
  • 9-(2-hydroxy-3-nonyl)adenine
  • Adenine
Topics
  • Adenine (analogs & derivatives, pharmacokinetics, pharmacology)
  • Adenosine Deaminase Inhibitors
  • Algorithms
  • Animals
  • Anti-HIV Agents (chemistry, pharmacokinetics)
  • Biological Availability
  • Biological Transport
  • Chemical Phenomena
  • Chemistry, Physical
  • Dideoxyadenosine (analogs & derivatives, chemistry, pharmacokinetics)
  • Enzyme Inhibitors (pharmacokinetics, pharmacology)
  • Intestinal Absorption (drug effects)
  • Intestines (drug effects, enzymology)
  • Male
  • Rats
  • Rats, Sprague-Dawley

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