R T DeGraw1, B D Anderson. 1. Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington 40536, USA.
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.
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.
Authors: J Van Gelder; P Annaert; L Naesens; E De Clercq; G Van den Mooter; R Kinget; P Augustijns Journal: Pharm Res Date: 1999-07 Impact factor: 4.200