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.
Bibliographical noteFunding Information:
The authors wish to thank Advanced Magnetics, Inc., the National Institutes of Health (PHS RO1-CA61908), the University of Minnesota Graduate School, the International Students Work Opportunity Program and the College of Pharmacy Research Funding for the financial support for this work. The authors also wish to acknowledge Matthew Radner for his excellent technical assistance.
- Biliary excretion
- Intestinal permeability
- Oral bioavailability