Abstract
The pharmacokinetics of a bispivaloylthioethyl prodrug of zidovudine monophosphate (AZTMP), bis(t-butyl-SATE)-AZTMP, and intracellular conversion of the prodrug to AZTMP were characterized following intravenous (i.v.) and oral (p.o.) administration of the prodrug to mice. Concentrations of bis(t-butyl-SATE)-AZTMP, AZTMP and zidovudine (AZT) in blood, red blood cells, plasma, brain and lymph nodes were determined by HPLC. Following i.v. administration of bis(t-butyl-SATE)-AZTMP, concentrations of the prodrug declined rapidly with low levels of the prodrug detected until 4 h. Both bis(t-butyl-SATE)-AZTMP and AZTMP were detected in brain 3 min after dosing. AZTMP was found 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. administration, i.v. administration of bis(t-butyl-SATE)-AZTMP produced lower peak concentrations of AZT in plasma, peripheral red blood cells, brain and lymph nodes. However, terminal half-lives of AZT were significantly prolonged following administration of the prodrug. Following p.o. administration of bis(t-butyl-SATE)-AZTMP, neither the prodrug nor AZTMP were detectable in whole blood. The conversion of AZT from bis(t-butyl-SATE)-AZTMP in plasma and peripheral red blood cells following p.o administration was 12.1% of that following i.v. administration of the prodrug. Bis(t-butyl-SATE)-AZTMP demonstrated promising potential for intracellular delivery of AZTMP. The prodrug also prolonged the retention of AZT in mice, and particularly increased delivery of AZT to the lymphatic and central nervous systems.