Disposition and oral bioavailability in rats of an antiviral and antitumor amino acid phosphoramidate prodrug of AZT-monophosphate

Purpose. The purpose of this study was to characterize the in vivo disposition of 3′-azido-2′-deoxythymidine-5′-methylamino-L- tryptophanylphosphoramidate (NMe-Trp-AZT), a potential pronucleotide of 3′-azido-2′-deoxythymidine monophosphate (AZT-MP). Methods. The in vitro metabolic stability of NMe-Trp-AZT was evaluated in a wide variety of tissue homogenates. NMe-Trp-AZT was administered orally (n = 3) to female Sprague-Dawley rats. Its biliary excretion and intestinal permeability were also studied. Results. Renal excretion of unchanged prodrug (16.4 ± 5.6% of the total dose administered intravenously), its conversion to AZT (12.1 ± 5.4% of total dose administered intravenously), and its biliary excretion (54.3 ± 4.9% of the total dose up to 4 h after intravenous administration) accounted for most of the elimination of NMe-Trp-AZT. Significant amounts of AZT were found in both plasma and urine after oral administration of the prodrug. The prodrug itself was not permeable through the small intestinal wall but was slowly converted to AZT-MP in gastric fluids at low pH. Conclusions. The NMe-Trp-AZT prodrug itself was not orally bioavailable because of poor intestinal permeability; however, AZT was readily available in the systemic circulation after the oral administration of the prodrug. Modification of the phosphoramidate to promote intestinal uptake should lead to enhanced oral bioavailability of this and other nucleoside phosphoramidate monoesters.