Carbonate Ester Prodrugs of Salicylic Acid: Synthesis, Solubility Characteristics, In Vitro Enzymatic Hydrolysis Rates, and Blood Levels of Total Salicylate Following Oral Administration to Dogs

Abstract

The methods of synthesis, solubilities, and partition coefficients for the ethyl-, butyl-,hexyl-, and 2,2,2-trichloroethylcarbonate esters of salicylic acid are reported. The solubility and partitioning characteristics of the ethyl- and trichloroethylcarbonates were similar to those of aspirin, whereas the butyl- and hexylcarbonates were more lipid soluble than aspirin. The in vitro hydrolysis rates of the compounds were also determined. The hydrolysis of the carbonate esters of salicylic acid were only slightly accelerated by 2 percent human plasma, and aspirin hydrolysis was not accelerated at all by this enzyme system. In the pseudocholinesterase and α-chymotrypsin systems, the hydrolysis of the butyl- and hexylcarbonates were accelerated to a much greater degree than those of the ethylcarbonate and aspirin. The results suggest that carbonates with 4 or 6 carbon alkyl chains fit the active sites of these esterolytic enzymes better than a carbonate with a 2 carbon alkyl chain or an acetate ester. Aspirin and the butyl-, hexyl-, and trichloroethylcarbonates were administered orally to dogs and the plasma levels of total salicylate were followed for 8 hr. The resulting blood level curves were virtually superimposable; all peaked at about 2 hr. and fell off at about the same rate. These results suggest that the prodrug carbonate esters are as readily absorbed as aspirin despite their different aqueous and lipid solubilities and that all the drugs including aspirin are converted to a common form, i.e. , tree salicylate, within 2—3 hr. after oral administration.