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Anticonvulsant activity of phenytoin-lipid conjugates, a new class of phenytoin prodrugs.
- Source :
-
The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 1995 Mar; Vol. 47 (3), pp. 197-203. - Publication Year :
- 1995
-
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.
- Subjects :
- Administration, Oral
Animals
Anticonvulsants metabolism
Anticonvulsants therapeutic use
Dimethyl Sulfoxide chemistry
Electroshock
Hydrolysis
In Vitro Techniques
Injections, Subcutaneous
Lipase chemistry
Lipids chemistry
Male
Mice
Pancreas enzymology
Pentylenetetrazole administration & dosage
Pentylenetetrazole pharmacology
Pentylenetetrazole therapeutic use
Phenytoin metabolism
Phenytoin therapeutic use
Prodrugs administration & dosage
Reference Standards
Seizures drug therapy
Structure-Activity Relationship
Anticonvulsants pharmacology
Lipid Metabolism
Phenytoin pharmacology
Prodrugs pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3573
- Volume :
- 47
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 7602480
- Full Text :
- https://doi.org/10.1111/j.2042-7158.1995.tb05778.x