PHARMACOKINETIC ANALYSIS OF DIETHYLCARBONATE PRODRUGS OF IBUPROFEN AND NAPROXEN

The pharmacokinetics of ibuprofen diethylcarbonate (ibudice) and napro xen diethythylcarbonate (napdice), two new diethylcarbonate prodrugs o f ibuprofen and naproxen, was investigated in dogs. The rationale for the development of ibudice and napdice was that esterification of the carboxylic moiety of the parent compounds would suppress gastrotoxicit y without adversely affecting their anti-inflamatory activity. In addi tion the biotransformation of the prodrugs to the parent compounds may be utilized to achieve rate and time controlled drug delivery of the active entities. Following oral administration the diethylcarbonate es ters were rapidly biotransformed to the parent compounds and no ibudic e or napdice was detected in the plasma. The relative bioavailability of ibuprofen and naproxen, following oral administration of ibudice an d napdice, was 96% and 74%, respectively, and the rate of absorption w as not significantly different from that obtained following oral dosin g of the parent compound. Stability studies in gastric and intestinal juice showed that, unlike napdice, ibudice was stable in gastric juice , with both prodrugs undergoing rapid biotransformation to their paren t compounds in intestinal juice. This rapid conversion led to the lack of sustained release performance following oral administration of ibu dice or napidice.