title: Phenytoin-lipid conjugates: chemical, plasma esterase-mediated, and pancreatic lipase-mediated hydrolysis in vitro.
abstract: Phenytoin-lipid conjugates obtained by covalent binding of hydroxymethylphenytoin to diacylglycerides and to 3-acyloxy-2-acyl-oxymethylpropionic acids formed dispersions with a particle size of 10-200 microns 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Münster, Germany.
authors.forename: G K
authors.initials: GK
authors.lastname: Scriba
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004950:Esterases / Q000097:blood / Q000737:chemistry*; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008049:Lipase / Q000737:chemistry*; D008055:Lipids / Q000097:blood / Q000737:chemistry*; D010179:Pancreas / Q000201:enzymology*; D010316:Particle Size; D010672:Phenytoin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D013657:Taurodeoxycholic Acid
chemical_list: D008055:Lipids; D011355:Prodrugs; D013657:Taurodeoxycholic Acid; D010672:Phenytoin; D004950:Esterases; D008049:Lipase