Improved delivery through biological membranes XXV. Enhanced and sustained delivery of trifluorothymidine to the brain using a dihydropyridine in equilibrium pyridinium salt type redox delivery system.

A series of alpha,alpha,alpha-trifluorothymidine (TFT) derivatives was designed and studied for brain-enhanced/specific delivery of this antiviral drug. The derivatives were esters involving one or both of TFT's hydroxy functions and N-methyl-dihydronicotinic acid. Such esters are subject to oxidative (to trigonelline) and hydrolytic metabolic transformations. Thymidine (T) was used as a model compound and the kinetics of the oxidative and hydrolytic conversion of some 16 derivatives of T and TFT were studied in various biological fluids. One compound, 3'-[O-(N-methyl-1,4-dihydronicotinoyl)]-5'-[O-(pivaloyl)]-TFT (14), was selected for in vivo studies. The compound appeared to cross the blood-brain barrier and to be converted in the brain by successive oxidative and hydrolytic processes to the 3'-[O-(N-methyl nicotinoyl)]TFT (17); this quaternary pyridinium salt was 'locked in' the brain and then further hydrolyzed in a sustained manner to release TFT, detected in measurable levels at least until 18 hours following the i.v. injection of 14. TFT was also identified as an in vitro degradation product in the different biological tissues and fluids. The results suggest that the dihydropyridine in equilibrium pyridinium salt redox delivery system can be successfully used for the brain delivery of antiviral agents that would not otherwise cross the blood-brain barrier.