PHENYTOIN
PHARMACOKINETIC PROPERTIES
Bioavailavility 85 % (70-100%). It is difficult to evaluate because of the drug’s capacitylimited metabolism.
ka = 50 mg/h saturable kinetics of absorption (zero order)
tmax = 3 - 12 h (dependent of the dose: increase with dose)
Vd = 0.65 L/Kg (0.6-0.8) in patients with normal renal function and with normal plasma
albumin concentrations.
Phenytoin binds primarily to albumin in plasma, being the bound fraction of 0.9
(0.69-0.95) under normal conditions.
Protein binding may be greatly reduced in the presence of the following factors:
Hypoalbuminaemia - for example, due to severe hepatic or renal disease
The last trimester of pregnancy, perhaps because of dilutional hypoalbuminaemia
Renal failure because of a reduced affinity of albumin for phenytoin
Displacement from protein binding sites by saliylates, valproic acid and
sulphonylureas
Renal excretion 1-5 %
Vmax.C ss
Km * D / 
D / 
 C ss 
ss
Vmax  D / 
Km  C
Biotransformation 70-90 % (saturable according Michaelis-Menten kinetics). In
steady-state:
The rate of phenytoin administration must be less than Vmax, otherwise steady-state will
never be achieved.


Adult patients:
Vmax = 6 mg/kg/day (5-15)
Km = 5.7 mg/L (1-20)
Paediatric patients:
Children from 6 months to 6 years
Children from 7 to 16 years
Children from 6 months to 16 years
C.V. = 50 %
C.V. = 30 %
Vmax = 12 mg/Kg/day (10-13)
Vmax = 9 mg/Kg/day (8-20)
Km = 4 mg/L (2-13)
Autoinduction by phenytoin should be considered during the treatment because enzyme
induction can occur after only a brief exposure to the drug.
C obs
C calcu 
0.25. ALB  0.1
Winter-Tozer equation is useful in predicting normalized phenytoin concentrations in
patients when unbound phenytoin concentrations are not readily available:
In addition, a graphical nomogram method to estimate the phenytoin free
concentration at any selected total plasma phenytoin and albumin concentrations has
been proposed (Pospisil J et al, 1994).
In patients with end-stage renal disease (creatinine clearance less tahn 10 mL/min), the
free fraction of phenytoin increases from 0.1 to approximately 0.2-0.35. The following
equation is useful in predicting normalized phenytoin concentrations for this kind of
patients:
C obs
C calcu 
0.1. ALB  0.1
(Vd * Km * ln( Cp0 / Cpt )  Vd * (Cp0  Cpt )
Vmax
The decline of phenytoin concentrations after discontinuation of therapy can be described
as follows:
t
Where Cp0 is the initial plasma concentration and Cpt is the plasma concentration at
the end of the time interval t.
Factors affecting phenytoin plasma concentration are:
Liver disease: acute hepatitis impairs the liver´s ability to metabolise phenytoin
Hypoalbuminaemia: Chronic liver disease, nephrotic syndrome, pregnacy and some
chronic illness can result in hypoalbuminemia which increases the free phenytoin
fraction and resutls in an increased rate of its metabolism.
Drug interactions:
Inhibition of metabolism: drugs inhibiting hepatic mono-oxygenase activity may
cause a reduction in the rate of phenytoin metabolism, which increase plasma drug
concentration and increase risk of toxicity:
Cimetidine Amidarone
Chlorpromazine Imipramine
Omeprazol Sulphonamides
H2-Antoagonis Disulfiram
Allopurinol
Azapropazone
Isoniazida
Metronidazol
Oral anticoagulants Thioridazine
Antituberculosis drugs
Stimulation of metabolism: drugs stimulating hepatic mono-oxygenase activity
which results in a decrease in plasma phnytoin concentration and the consequent risk
of breakthrought seizures, are the following:
Carbamazepine
Felbamate
Tiagabine
Diazepam
Phenobarbital
Lamotrigine
Dexamethasone
Chlordiazipoxide
Rifampicine
Topiramate
Nitrofurantoin
Displacement from protein binding: drugs displacing phenytoin from its binding
sites on plasma albumin, increasing the fraction of drug unbound which alters the
interpretation of the total plasma phenytoin concentration are:
Aspirin
Sodium Valproate
ADVERSE EFFECTS
They are related to plasma concentrations:
Plasma levels (mg/L) Symptom
20-30
20-30
30-40
30-40
> 40
Mental changes
Nystagmus
Ataxia
Long term adverse effects of Phenytoin
Gingival hyperplasia
Coarsening of facial features
Acne
Hirsutism
Folate deficiency
Vitamin D deficiency
THERAPEUTIC RANGE
Therapeutic range accepted, in the absence of complicating factors, is between 10-20
mg/L (total plasma level) but it should be only used as a guide to the treatment of
epilepsy. This range changes for particular seizure syndromes and for patients with
different degrees of seizure activity within each seizure syndrome type. So, there are
evidence that bilateral tonic-clonic seizures are controlled by phenytoin at lower plasma
concentration than those required to control partial seizures. Some patients can be
completely controlled at plasma concentrations below 10 mg/L but other patients with
severe epilepsy may require concentrations in excess to upper limit (20 mg/L) and
patient tolerate the drug well.
The therapeutic range of total plasma concentrations falls in renal failure and when a
hypoalbuminaemia exits.
Patients
Adults and children
Newborns and children under 3 years
Endstage renal disease or hypoalbuminaemia
Endstage renal disease and hypoalbuminaemia
Liver disease
Acute hepatitis
Therapeutic range
10-20 mg/L
6-14 mg/L
5-10 mg/L
3-7 mg/L
7-14 mg/L
8-16 mg/L
Since about 10 % of phenytoin is unbound in the plasma, a therapeutic range for free
phenytoin of 1-2 mg/L has been recommended.
Knowledge of the plasma concentration that produces a good response in the particular
patient (the so-called "individual therapeutic concentration" will provide an important
reference in making further dosage adjustment.
INDICATIONS FOR MONITORING
At the initiation of the therapy, in order to achieve a plasma concentration within the
therapeutic range. The concentration at which seizure control has been attained without
adverse effects serves as the reference value.
When seizures reccur after a period of control in order to know if plasma concentration is
lower than that control was obtained.
When there is intercurrect illness (AIDS patients, hypoalbuminemia, renal impairment...)
or a change in physiological state exists (age, pregnancy...)
When drug toxicity is suspected
When phenytoin therapy is about to be withdrawn
Intervals during the course of therapy
SAMPLING TIMES
The timing of plasma sampling for phenytoin is not critical, because the fluctuation in its
plasma concentration is relatively small, even when dosage is once daily. That is why
individual sample is usually drawn at steady-state and at the end of the dosage interval.
This concentration is minimally influenced by variations in drug absorption rate and it
can be assumed that aproximates the average steady-state concentrations.
In those patients requiring rapid achievement and maintenance of therapeutic phenytoin
concentrations , it is usal to monitor phenytoin plasma level within two to three days of
therapy initiation (non steady-state situation).
KINETIC MODEL
One-compartment model with zero order absorption and Michaelis-Menten elimination.
DOSAGE RECOMMENDATIONS
Population
Adults
Children < 3 months
Children 6 months-6 years
Pregnancy
Maintenance dose
5-7 mg/Kg/day
3-5 mg/Kg/day
5-15 mg/Kg/day
5-15 mg/Kg/day
Dosage interval
12 (8, 12 and 24) hours
8 hours
12 (8 and 12) hours
12 (8 and 12) hours
Small changes in phenytoin dosage may cause large changes in plasma phenytoin
concentrations, so they should be done with precaution.
There are a number of graphic approaches so-called "nomograms" that can be used to
estimate individual dosage requirements. They require information from one, two or
more steady-sate plasma concentrations in the patient and may be a practical aid in adult
and pediatric practice
Clinical utility shown of Bayesian forecasting methods: acceptable predictive
performance in non-steady-state and steady-state situations.
OBSERVATIONS
Monitoring of free phenytoin concentrations may be beneficial in patients with AIDS,
hypoalbuminemia and renal impairment. Besides, when the patient receive another drug
such as Valproic acid which can compete with phenytoin for protein binding.
Time to reach steady-state increases with dose. The time required to achieve 90% of
t90% 
Km.Vd
* 2.3 *Vmax  0.9( Dose / day)
(Vmax  ( Dose / day)) 2
steady state, can be calculated as follows:
A nomogram has been developed to help the physician to decide whether a measured
plasma concentration can be regarded in steady-state situation.
Long term treatment with phenytoin may result in a folate dependent megaloblastic
anemia, which is treated with folic acid (folic acid increasess phenytoin clearance) so
plasma phenytoin conentration will be reduced and this may result in breakthrough
seizures.
There is a complicated interaction between phenytoin and sodium valproate which
displaces phenytoin from protein binding sites and thus changes the therapeutic range,
but also inhibits phenytoin metabolism, making difficult to interpret plasma phenytoin
concentrations in patients taking valproate.
POPULATION MODELS
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