In vitro and in vivo pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog 3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate] (Compound 003).

The pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog Compound 003 (3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate], CAS 149560-32-7) were studied in both human cancer cells and mice. In mice, Compound 003 was rapidly converted into ala-AZT-MP (CAS 209214-06-2) and zidovudine (azidothymidine, AZT, CAS 30516-87-1). Maximum ala-AZT-MP concentrations were reached almost immediately (tmax < 5 min), while 50.4 min and 143.5 min were required to reach maximum AZT concentrations after intravenous and oral administration, respectively. The results indicate that paraoxon-sensitive carboxylesterases play an important role in the conversion of Compound 003 to ala-AZT-MP. This study provides the basis for future preclinical as well as clinical pharmacodynamic studies of Compound 003.