title: Anticonvulsant activity of phenytoin-lipid conjugates, a new class of phenytoin prodrugs.
abstract: The anticonvulsant activity of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxy-methylphenytoin to dimyristoylglycerides via a succinidyl linkage, to 2-(1,3-dimyristoylglyceryl)butyric acid and to 3-myristoyl-2-myristoylmethylpropionic acid was evaluated in the maximal electroshock (MES) test and the seizure threshold test with subcutaneous pentetrazol. The phenytoin-lipid conjugates were less active than the parent drug in the MES test after intraperitoneal administration as suspensions, but exhibited comparable activity when injected as a solution in dimethylsulphoxide. They also protected mice from MES-induced seizures following oral administration of aqueous suspensions of the compounds or when incorporated into emulsions. The anticonvulsant activity could be correlated to in-vitro pancreatic lipase-mediated hydrolysis. The bis-deacyl derivatives were at least as active but in some cases also more toxic than phenytoin. Oral administration of two of the lipid conjugates resulted in a faster onset of the anticonvulsant activity compared with the administration of an equimolar dose of phenytoin itself. All compounds were inactive in the subcutaneous pentetrazol test. It is concluded that the lipids act as prodrugs of phenytoin, which is generated by lipolysis upon oral administration.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Münster, Germany.
authors.forename: G K
authors.initials: GK
authors.lastname: Scriba
authors.forename: D M
authors.initials: DM
authors.lastname: Lambert
authors.forename: J H
authors.initials: JH
authors.lastname: Poupaert
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004597:Electroshock; D006868:Hydrolysis; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D008049:Lipase / Q000737:chemistry; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D010179:Pancreas / Q000201:enzymology; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010672:Phenytoin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D012015:Reference Standards; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D008055:Lipids; D011355:Prodrugs; D010672:Phenytoin; D008049:Lipase; D010433:Pentylenetetrazole; D004121:Dimethyl Sulfoxide