Fosphenytoin prodrug

Fosphenytoin Fosphenytoin is a water-soluble, phospho-ester prodrug of phenytoin that is rapidly converted to phenytoin in the body. It is compatible with most IV solutions and is well tolerated as an IM injection, even with the large volumes associated with loading doses (20 to 30 mL).19 It is dosed in phenytoin equivalents (PE), and it can be infused three times as fast as phenytoin, up to 150 mg PE/minute. The loading dose for patients not taking phenytoin is 15 to 20 mg PE/kg. It can be an advantage to use IM fosphenytoin when IV access cannot be obtained immediately and in patients with poor venous access. Although it has fewer cardiovascular side... 

Fosphenytoin, the water-soluble phosphate ester of phenytoin, is a phenytoin prodrug. 

Serious medication errors, including some leading to death, have resulted from the interpretation of the Cerebyx product labeling. The terminology on the label, which previously indicated the concentration as being 50 mg of phenytoin equivalents (PE) per milliliter, was misinterpreted as the total number of PEs per vial. Furthermore, health professionals were reportedly confused by the expression phenytoin equivalents, a prodrug concept introduced for this product. As a result, massive fosphenytoin overdoses were mistakenly administered. 

Prodrug, fosphenytoin rapidly converted to phenytoin in vivo minimal activity before conversion water soluble, thus more suitable for parenteral applications does not require cardiac monitoring can be administered at faster rate no IV filter required compatible with both saline and dextrose mixtures requires refrigeration... 

After oral administration peak plasma concentration of phenytoin usually takes 2 to 4 hours with a second peak at 10 to 12 hours. When administered intramuscularly, pheny-toin is eventually absorbed completely, the drug first crystallises out at the injection site and then slowly redissolves in tissue fluids before entering into the circulation. As a result absorption of phenytoin by IM route is too slow to produce a reliable effect. In contrast a phosphate prodrug, fosphenytoin, is more soluble and is well absorbed after IM administration. 

Phenytoin is a diphenyl-substituted hydantoin with the structure shown. It has much lower sedative properties than compounds with alkyl substituents at the 5 position. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use this phosphate ester compound is rapidly converted to phenytoin in the plasma. 

Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs this route of administration is not recommended for phenytoin. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration. 

For example, fosphenytoin is designed as a disodium salt ester prodrug of phenytoin (Fig. 3.9) to overcome parenteral delivery problems... 

Fosphenytoin, a prodrug of phenytoin, is soluble in water, easier and safer to administer its conver-tion in the blood to phenytoin is rapid and it may be used as an alternative to phenytoin for status epilepticus (Table 20.1). 

Water-soluble prodrugs. These include water-soluble salts, esters (e.g., fosphenytoin Cerebyx ) or complexes. 

Fosphenytoin is a prodrug, a compound that undergoes chemical conversion in the body to become the therapeutically active compound phenytoin. Cerebyx dosage will continue to be expressed in PEs. This terminology was adopted in an effort to simplify therapeutic conversions between phenytoin sodium and fosphenytoin sodium (i.e., 500 mg of phenytoin sodium injection is equal to 500 mg PE of fosphenytoin sodium injection). The manufacturer pointed out that by using PEs, prescribers will not have to make dosing... 

Phenytoin is the only widely used hydantoin and, unless otherwise specified, effects discussed here refer to phenytoin. Other hydantoin derivatives include ethotoin (rINN), mephenytoin (rINN), and albutoin (rINN) (all of which are obsolete), and fosphenytoin (rINN). The latter is a water-soluble prodrug that is rapidly hydrolysed to phenytoin after intravenous or intramuscular injection. It causes fewer adverse reactions near the injection site (pain, phlebitis, tissue necrosis, purple hand syndrome) than phenytoin. 

Intravenous phenytoin has been associated with fatal hemodynamic complications and serious reactions at the injection site, including skin necrosis and amputation of extremities. Fosphenytoin, a phenytoin prodrug, has the same pharmacological properties but none of the injection site and cardiac rhythm complications after intravenous administration (64). 

Either phenytoin or fosphenytoin is then administered. Fos-phenytoin Is a water-soluble prodrug of phenytoin and causes less hypotension and cardiac arrhythmias than phenytoin. Cardiovascular status should be carefully monitored, especially for hypotension and arrhythmias. 

Chemical Abstracts Service Registry Numbers CAS 57-41-0 CAS 630-93-3 Synonyms Diphenylhydantoin (DPH) 5,5-Dip-henylhydantoin, 5,5-Diphenylimidazolidine-2, 4-dione Dilantin Infatabs Fenitoina Phenantoi-num Phenytoin sodium (92% phenytoin) Diphenylhydantoin sodium Diphenin Phenytoinum natricum Soluble phenytoin Dilantin Epanu-tin Diphenylan Fosphenytoin is a water-soluble prodrug of phenytoin suitable for rapid intravenous administration Chemical/Pharmaceutical/Other Class Hydan-toin (a synthetic chemical that is structurally similar to barbituric acid)... 

In addition to an extensive summary provided previously on this moiety (8), Brouillette et al. (209) employed comparative molecular field analysis (CoMFA), a three-dimensional structure-activity technique, to provide a new potential anticonvulsant, 2-hydroxy-2-phe-nylnonanamide (40), whose Na-i-channel inhibition (IC50 = 9 fiM) compared favorably to 40 yM for phenytoin (1). This study suggested that the hydantoin ring system is not necessary in Na+channel binding. Research on water-soluble prodrugs of phenytoin has continued since the work by Stella, which led to the synthesis of fosphenytoin (Id) (8,209-215). A... 

If oral administration is not feasible, intravenous administration of phenytoin is preferred over intramuscular administration. Fos-phenytoin is a prodrug for phenytoin and is available as a parenteral dosage form. It is very water-soluble and is converted rapidly to phenytoin systemically. Fosphenytoin can be given rapidly intravenously and intramuscularly with reliable absorption and minimal pain. It is significantly better tolerated than phenytoin. 

The low aqueous solubility of phenytoin hindered its intravenous use. Fosphenytoin (CEREBYX), a water soluble prodrug, is rapidly converted into phenytoin by phosphatases in hver and erythrocytes. Fosphenytoin is extensively (95-99%) bound to plasma proteins, primarily albumin. This binding is saturable, and fosphenytoin displaces phenytoin from binding sites. Fosphenytoin is useful for adults with partial or generalized seizures when intravenous or intramuscular administration is indicated. 

I. Pharmacology. The neuronal membrane-stabilizing actions of phenytoin make this a popular drug for sustained control of aoute and ohronic seizure disorders and a useful drug for certain cardiac arrhythmias. Because of the relatively slow onset of anticonvulsant action, phenytoin is usually administered after diazepam. At serum concentrations considered therapeutic for seizure control, phenytoin acts similarly to lidocaine to reduce ventricular premature depolarization and suppress ventricular tachycardia. After intravenous administration, peak therapeutic effects are attained within 1 hour. The therapeutic serum concentration for seizure control is 10-20 mg/L. Elimination is nonlinear, with an apparent half-life averaging 22 hours. Fosphenytoin, a prodrug of phenytoin for intravenous use, is converted to phenytoin after injection, with a conversion half-life of 8-32 minutes. 

Fosphenytoin is a prodrug of phenytoin, which is rapidly and completely hydrolysed to phenytoin in the body. It is predicted to interact with other drugs in the same way as phenytoin. No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. ... 

Cwik, M.J. Liang, M. Deyo, K. Andrews, C. Fischer, J. Simultaneous rapid high-performance liquid chromatographic determination of phenytoin and its prodrug, fosphenytoin in human plasma and ultrafiltrate, J.Chromatogr.B, 1997, 693, 407-414. 

Status epilepticus is traditionally defined as a situation where there is continuous seizure activity for a period of 30 minutes or where there are a continuous series of seizures during which the sufferer does not regain consciousness. More recently, it has been suggested that any continuous seizure period of longer than 5 minutes should be classified as status epilepticus. In these situations the treatment employed may well consist of one of the previously indicated antiepileptic dmgs such as clonazepam (Fig. 13.15), phenobarbital and phenytoin (Fig. 13.15) or alternatively diazepam, fosphenytoin (a prodrug of phenytoin), loraze-pam, midazolam and paraldehyde (Fig. 13.16) may be employed. For the drugs used in the treatment of status epilepticus, the formulation and dose differ from conventional doses due to the situation and thus many of these will be administered by intravenous injection, intravenous infusion, buccal or rectal administration. 

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