Pharmacology of ACC‐9653 (Phenytoin Prodrug)

Abstract

ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin Blocks the Reversal of a Classically Conditioned Discriminative Eyeblink Response in Rabbits

“…Fosphenytoin is a prodrug that is enzymatically converted to PHT by phosphorylases present in most tissues and blood (16,17). Shith et al (18) reported that on an , equimolar basis PHT and fosphenytoin have equivalent anticonvulsant activity against seizures induced by maximal electroshock in mice. Moreover, fosphenytoin is freely soluble in aqueous solutions (1 9) and can therefore be administered in peripheral tissues with minimal discomfort.…”

Bioavailability and Anticonvulsant Activity of 2-Cyanoguanidinophenytoin, a Structural Analogue of Phenytoin

“…[15][16] Recrystallization from DMF/water afforded 14 g (50%): mp 254-257°C dec (lit. 15 10.14 g of potassium hydroxide (178 mmol), and 2.5 g of PEG 600 were heated at 100°C for 2 h in a twophase system consisting of 200 mL of water and 200 mL of 1-butanol. After cooling, the mixture was filtered and acidified with acetic acid to give a precipitate, which was washed with water and recrystallized X Abstract published in Advance ACS Abstracts, September 1, 1996. to give 16.5 g (59%).…”

“…4,5 In order to overcome this drawback, several phenytoin prodrugs, mostly esters of 3-(hydroxymethyl)phenytoin, have been investigated. [6][7][8][9] Fosphenytoin (ACC-9653) 10 is currently under clinical investigation for the treatment of the status epilepticus. 11 As an alternative approach, structural analogues of phenytoin such as 5,5-diphenyl-2-thiohydantoin, 12 4,4-diphenyl-1,2,5-thiazolidin-3-one 1,1-dioxide, 13 and 5,5-diphenyl-2-iminohydantoin 14 have been prepared but showed only a low anticonvulsant activity in animal models if any activity was noted at all.…”

Incidence and risk factors of hypotension after intravenous fosphenytoin administration

“…1 FOS is a water-soluble, disodium phosphate ester of phenytoin that can be administered parenterally without a propylene glycol vehicle. 2 Thus, FOS is safer to administer than phenytoin because propylene glycol likely causes the hypotension and cardiac arrhythmias reported in patients who received phenytoin. 3 Indeed, it is generally accepted that FOS is associated with fewer significant adverse cardiovascular effects than phenytoin.…”