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Pharmacology: Pharmacodynamics: Phenytoin is an anticonvulsant drug, which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at the synaptic levels. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.
Pharmacokinetics: Phenytoin is a weak acid and has limited hydrosolubility, even in the intestine. The compound undergoes a slow and somewhat variable absorption after oral administration. After absorption is complete, it is rapidly distributed into all tissues.
The plasma half-life of phenytoin in man averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic drug levels are achieved at least 7 to 10 days after initiation of therapy with recommended doses of 300 mg/day. For oral formulations of phenytoin, peak serum levels occur 1½ to 3 hours after administration. Phenytoin has an apparent volume of distribution of 0.6 L/kg and is highly bound (90%) to plasma proteins, mainly albumin.
Free phenytoin levels may be altered in patients whose protein-binding characteristics differ from normal. Phenytoin is distributed into the cerebrospinal fluid (CSF), saliva, semen, gastrointestinal fluids, bile, and breast milk. The concentration of phenytoin in the CSF, brain, and saliva approximates the level of free phenytoin in plasma.
Phenytoin is biotransformed in the liver by oxidative metabolism. The major pathway involves 4-hydroxylation, which accounts for 80% of all metabolites. CYP2C9 plays the major role in the metabolism of phenytoin (90% of net intrinsic clearance), while CYP2C19 has a minor involvement in this process (10% of net intrinsic clearance). This relative contribution of CYP2C19 to phenytoin metabolism may, however, increase at higher phenytoin concentrations.
Because the cytochrome systems involved in phenytoin hydroxylation in the liver are saturable at high serum concentrations, small incremental doses of phenytoin may increase the half-life and produce very substantial increases in serum levels when these are in or above the upper therapeutic range. The steady-state level may be disproportionately increased with resultant intoxication from an increase in dosage of 10% or more. The clearance of phenytoin has been shown to be impaired by CYP2C9 inhibitors, such as phenylbutazone and sulfaphenazole. Impaired clearance has also been shown to occur in patients administered CYP2C19 inhibitors, such as ticlopidine.
Most of the drug is excreted in the bile as inactive metabolites, which are then reabsorbed from the intestinal tract and eliminated in the urine partly through glomerular filtration, but more importantly via tubular secretion. Less than 5% of phenytoin is excreted as the parent compound.
In most patients maintained at a steady dosage of an oral formulation, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low serum levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, congenital enzyme deficiency or drug interactions, which result in metabolic interference. Patients with large variations in phenytoin serum levels, despite standard doses, present a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. When they are necessary, they should be obtained at least 7 to 10 days after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady state will have been achieved. Trough levels, obtained just prior to the patient's next scheduled dose, provide information about clinically effective serum level range and confirm patient compliance. Peak drug levels, obtained at the time of expected peak concentration, indicate an individual's threshold for emergence of dose-related side effects.
Pharmacokinetic Interaction: Co-administration of nelfinavir tablets (1250 mg twice a day) with phenytoin capsule (300 mg once a day) did not change the plasma concentration of nelfinavir. However, co-administration of nelfinavir reduced the AUC values of phenytoin (total) and free phenytoin by 29% and 28%, respectively.
Special Populations: Patients with Renal or Hepatic Disease: see General under Precautions.
Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see Dosing in Special Populations-Elderly Patients under Dosage & Administration).
Toxicology: Preclinical safety data: Carcinogenesis: In a transplacental and adult carcinogenicity study, phenytoin was administered in diet at 30 to 600 ppm to mice and 240 to 2400 ppm to rats. Hepatocellular tumors were increased at the higher doses in mice and rats. In additional studies, mice received 10 mg/kg, 25 mg/kg, or 45 mg/kg and rats were given 25 mg/kg, 50 mg/kg, or 100 mg/kg in the diet for 2 years. Hepatocellular tumors in mice increased at 45 mg/kg. No increases in tumor incidence were observed in rats. These rodent tumors are of uncertain clinical significance.
Genetic toxicity studies showed that phenytoin was not mutagenic in bacteria or in mammalian cells in vitro. It is clastogenic in vitro but not in vivo.
