COMPARISON OF THE DISPOSITION OF ESTER PRODRUGS OF THE ANTIVIRAL AGENT 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE [PMEA] IN CACO-2 MONOLAYERS

Purpose. To evaluate the potential of several bis-ester prodrugs of th e antiviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) to enhance the oral absorption of PMEA. Methods. Caco-2 monolayers we re used to estimate intestinal transport and metabolism of the bis(piv aloyloxymethyl)-ester [bis(POM)-] and a series of bis(S-acyl-2-thioeth yl)-esters [bis(SATE)-] of PMEA. An LC-MS method was used for the iden tification of unknown metabolites which were formed from the SATE-este rs.Results. During transport across Caco-2 monolayers, all esters were extensively degraded as could be concluded from the appearance of the mono-ester and free PMEA in apical as well as basolateral compart men ts. Incubation of SATE-esters with the monolayers resulted in the form ation of two additional metabolites, which were identified as 2-thioet hyl-PMEA and its dimerisation product. All eater prodrugs resulted in enhanced transepithelial transport of total PMEA (i.e. the bis-esters and their corresponding metabolites, including PMEA), but significant differences could be observed between the various esters. Transport of total PMEA ranged from 0.4 +/- 0.1% for the bis[S(methyl) ATE]-ester to 15.3 +/- 0.9% for the more lipophilic bis[S(phenyl)ATE]-PMEA. A rel ationship between total transport of the esters and their lipophilicit y (as estimated by their octanol/water partition coefficient) was esta blished (r(2) = 0.87). Incubation of prodrug esters with homogenates f rom Caco-2 cells showed large differences in susceptibility of the com pounds to esterases, the half-lives of the bis-esters varying from 4.3 +/- 0.3 min for the bis[S(phenyl)ATE]-PMEA to 41.5 +/- 0.8 min for it s methyl analogue. In addition, intracellularly formed PMEA was observ ed to be further converted by the cells to the diphosphorylated PMEA ( PMEApp). Conclusions. Several SATE-esters of PMEA can be considered as potential alternatives to bis(POM)-PMEA, due to enhanced epithelial t ransport, sufficient chemical and enzymatic stability and adequate rel ease of PMEA. Toxicological studies as well as in vivo experiments are required in order to further explore the potential of those SATE-este rs as prodrugs for oral delivery of PMEA.