Enhanced Oral Bioavailability of 2′-β-fluoro-2′,3′-dideoxyadenosine (F-ddA) Through Local Inhibition of Intestinal Adenosine Deaminase

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-β-fluoro-2′,3′-dideoxyadenosine (F-ddA) is an adenosine deaminase (ADA) activated prodrug of 2-β-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.