Abstract | PURPOSE: 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.
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Authors | R T DeGraw, B D Anderson |
Journal | Pharmaceutical research
(Pharm Res)
Vol. 18
Issue 9
Pg. 1270-6
(Sep 2001)
ISSN: 0724-8741 [Print] United States |
PMID | 11683239
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Adenosine Deaminase Inhibitors
- Anti-HIV Agents
- Enzyme Inhibitors
- lodenosine
- Dideoxyadenosine
- 9-(2-hydroxy-3-nonyl)adenine
- Adenine
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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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