Pharmacokinetics of salicylate ester prodrugs of cyclic HPMPC in dogs

A series of aryl ester prodrugs of cyclic HPMPC have been synthesized and t heir physicochemical properties, pharmacokinetics and metabolism have been evaluated. Chemical stability was dependent on the orientation of the exo-c yclic ligand; the equatorial isomers were 5.4 to 9.4 fold more reactive tha n the axial isomers. The oral bioavailability of cyclic HPMPC from the aryl ester prodrugs ranged from 11.2% for o-pentylphenyl cyclic HPMPC to 46.3% for butylsalicylyl cyclic HPMPC. Cyclic HPMPC was the major metabolite obse rved for all the salicylyl ester prodrugs. Cidofovir accounted for 2 to 12% of the total plasma AUC for butyl, cyclohexyl- and phenethyl-salicylyl est ers of cyclic HPMPC. Intact prodrug or the corresponding monosalicylyl este rs of cidofovir each accounted for less than 10% of the total AUC for salic ylyl ester prodrugs.