1: J Pharm Pharmacol 1995 Mar;47(3):197-203
Anticonvulsant activity of phenytoin-lipid conjugates, a new class of phenytoin
prodrugs.
Scriba GK, Lambert DM, Poupaert JH
Department of Pharmaceutical Chemistry, School of Pharmacy, University
of Munster, Germany.
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.
PMID: 7602480, UI: 95326018