Pharmacokinetics of bis(t-butyl-SATE)-AZTMP, a bispivaloylthioethyl prodrug for intracellular delivery of zidovudine monophosphate, in mice

The pharmacokinetics of a bispivaloylthioethyl prodrug of zidovudine monoph osphate (AZTMP), bis(t-butyl-SATE)-AZTMP, and intracellular conversion of t he prodrug to AZTMP were characterized following intravenous (i.v.) and ora l (p.o.) administration of the prodrug to mice. Concentrations of bis(t-but yl-SATE)-AZTMP, AZTMP and zidovudine (AZT) in blood, red blood cells, plasm a, brain and lymph nodes were determined by HPLC. Following i.v. administra tion of bis(t-butyl-SATE)-AZTMP, concentrations of the prodrug declined rap idly with low levels of the prodrug detected until 4 h. Both bis(t-butyl-SA TE)-AZTMP and AZTMP were detected in brain 3 min after dosing. AZTMP was fo und in both plasma and peripheral red blood cells, peaking at approximately 30 min and remaining detectable until 2 h. No AZTMP was detected in lymph nodes. Compared to the pharmacokinetics of AZT following its i.v. administr ation, i.v. administration of bis(t-butyl-SATE)-AZTMP produced lower peak c oncentrations of AZT in plasma, peripheral red blood cells, brain and lymph nodes. However, terminal half-lives of AZT were significantly prolonged fo llowing administration of the prodrug. Following p.o. administration of bis (t-butyl-SATE)-AZTMP, neither the prodrug nor AZTMP were detectable in whol e blood. The conversion of AZT from bis(t-butyl-SATE)-AZTMP in plasma and p eripheral red blood cells following p.o administration was 12.1% of that fo llowing i.v. administration of the prodrug. Bis(t-butyl-SATE)-AZTMP demonst rated prom ising potential for intracellular delivery of AZTMP. The prodrug also prolonged the retention of AZT in mice, and particularly increased de livery of AZT to the lymphatic and central nervous systems.