In vitro and in vivo study of water-soluble prodrugs of dexanabinol

Trialkylammonium acetoxymethyl esters of dexanabinol were synthesized and e valuated as water-soluble prodrugs. Syntheses were performed by conventiona l methods; solubility in water and stability in buffers and human plasma we re determined by HPLC, and in vivo tissue distribution studies were perform ed in a rat model. Most of the new derivatives were soluble in water (simil ar to 50 mg/mL). They were relatively stable in water, while rapidly hydrol yzed in human plasma. Distribution studies indicated that peak concentratio ns of drug both in blood (30 mu g/mL) and brain (2 mu g/mL) were rapidly (5 min) achieved after iv administration of a selected prodrug to rats. The b lood concentration decreased faster than brain levels which were detectable even after 24 h. Some of the examined esters could be further developed as water soluble prodrugs of dexanabinol.