PHYSICOCHEMICAL PROPERTIES, BIOCONVERSION AND DISPOSITION OF LIPOPHILIC PRODRUGS OF 2',3'-DIDEOXYCYTIDINE

Lipophilic prodrugs of 2',3'-dideoxycytidine (ddC), 4,5'-diacetyl-ddC (DAC), 4,5'-ditrimethylacetyl-ddC (DTMAC), 4,5'-dicyclopentylpropionyl -ddC (DCYPP) and 5'-cholesteryl-ddC (CHOL), were evaluated for their u tility in improving brain delivery of the parent nucleoside. The lipop hilicity of the prodrugs was greater, compared to ddC, with partition coefficient values increasing from 0.03 for ddC to 0.37, 28, 63 and 48 3 for DAC, DTMAC, DCYPP and CHOL, respectively, Aqueous solubility was decreased proportionally to the increase in lipophilicity, Bioconvers ion studies were performed in phosphate buffer (pH 7.4), human serum, mouse serum, and mouse brain and liver homogenates, Whereas CHOL was s table in vitro in all media, DAC, DTMAC and DCYPP exhibited stability only in buffer, indicating that the hydrolytic reaction for these comp ounds was, predominately, enzymatically triggered. DCYPP was rapidly h ydrolysed in mouse serum and liver and brain homogenates with degradat ion half-life values of 0.04, 0.35 and 0.34 h respectively. DAC had a longer half-life in mouse serum than did DTMAC (0.82 h vs, 0.38 h), ho wever, in mouse brain homogenate DTMAC (t(1/2) = 3.9 h) was more stabl e than DAC (t(1/2) = 1.6 h). Both of these prodrugs were rapidly metab olized in the mouse liver homogenate with halt-life values of 0.36 h f or DAC and 0.23 h for DTMAC, In-vivo studies performed for ddC, DAC an d DTMAC in mice showed that the relative brain exposure (r(e)) of ddC was not improved by administering the prodrugs. DTMAC yielded a r(e) v alue of 0.023 which was similar to that for ddC (r(e) = 0.028), while no ddC was detected in brain after DAC administration. Thus, although all of the prodrugs were more lipophilic than ddC, delivery of ddC to the brain was not enhanced in vivo.