PHENYTOIN LIPID CONJUGATES - CHEMICAL, PLASMA ESTERASE-MEDIATED, AND PANCREATIC LIPASE-MEDIATED HYDROLYSIS IN-VITRO

Phenytoin-lipid conjugates obtained by covalent binding of hydroxymethylphenytoin to diacylglycerides and to 3-acyloxy-2-acyloxymethylpropionic acids formed dispersions with a particle size of 10-200 mum when briefly sonicated in a sodium taurodeoxycholate-containing ethanol-water mixture. In contrast to the corresponding bis-deacyl derivatives, the lipids were not significantly hydrolyzed in aqueous buffers and in plasma. Incubation with pancreatic lipase yielded primarily the bis-deacyl compounds, which are comparable to monoglycerides, and subsequently liberated phenytoin. The glyceride-derived prodrugs were better substrates for the enzyme than the 3-acyloxy-2-acyloxymethyl-propionic acid derivatives. It is concluded that the phenytoin lipid conjugates are hydrolyzed by pancreatic lipase in a similar manner as natural triglycerides.