Synthesis and Pharmacokinetics of a Dihydropyridine Chemical Delivery System for the Antiimmunodeficiency Virus Agent Dideoxycytidine

Article abstract of DOI:10.1021/jm00057a002

In order to explore the possibility that a dihydropyridine/pyridinium redox chemical delivery system might enhance significantly the brain uptake of the anti-HIV agent dideoxycytidine (DDC), we prepared a DDC derivative wihich bore the 1,4-dihydro-1-methyl-3-pyridylcarbonyl moiety at both the cytidine exocyclic amino moiety and the sugar 5'-hydroxyl function; namely 5',4N-bis<(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl>-2',3'-dideoxycytidine (2).In cell-free extracts of rat brain tissue, compound 2 was readily converted to free DDC by stepwise oxidation and hydrolysis of the dihydropyridyl groups.Time-dependent plasma and brain concentrations of DDC and 2 were determined following iv administration of 2 (49.3 mg/kg) to rats.Compound 2 could be detected in brain, reaching peak concentrations of 7.7 +/- 2.9 nmol/g at 15 min.Low levels of DDC also were detected with a peak concentration of 1.4 +/- 0.5 nmol/g at 240 min after injection.The brain/plasma concentration integral of compound 2 was 0.95 whereas that for DDC in brain as a ratio of combined DDC and compound 2 levels in plasma was 0.24.Despite this, brain concentrations remained low and not significantly different from those achieved following administration of DDC alone.