Clinical Pharmacokinetic Phenytoin: Rahmad Abdillah., M.Si, Apt

CLINICAL PHARMACOKINETIC
PHENYTOIN
Rahmad Abdillah., M.Si, Apt

• Phenytoin is a hydantoin compound related to the
barbiturates that are used for the treatment of seizures.
• It is an effective anticonvulsant for the chronic treatment

of tonic-clonic (grand mal) or partial seizures and the
acute treatment of generalized status epilepticus
• The antiseizure activity of phenytoin is related to its

ability to inhibit the repetitive firing
• of action potentials caused by prolonged depolarization
of neurons
Phenytoin ®
(Dilantin )
• Mechanism of Action:
– Na+ channel blocker in motor cortex; decreases
hyperexcitability of neuron
• Indications:
FDA-approved
• Generalized tonic-clonic seizures
• Complex partial seizures
• Status epilepticus
• Seizure prophylaxis following neurosurgery
Therapeutic And Toxic Concentrations
• The usual therapeutic range for total phenytoin serum
concentrations when the drug is used in the treatment of
seizures is 10–20 μ/mL
• At total phenytoin concentrations above 20 μg/mL, nystagmus

may occur and can be especially prominent upon lateral gaze
• When total concentrations exceed 30 μg/mL, ataxia, slurred

speech, and/or incoordination similar to ethanol intoxication
can be observed.
•
• If total phenytoin concentrations are above 40 μg/mL, mental
status changes, including decreased mentation,severe
confusion or lethargy, and coma are possible
• Because phenytoin follows nonlinear or
saturable metabolism pharmacokinetics, it is
possible to attain excessive drug concentrations
much easier than for other compounds that
follow linear pharmacokinetics
Disease States and Conditions that Alter
Phenytoin Plasma Protein Binding
• Patients with albumin concentrations between 2.5–3 g/dL
typically have phenytoin unbound fractions of 15–20%,
while patients with albumin concentrations between 2.0–
2.5 g/dL often have unbound phenytoin fractions >20%.
• Phenytoin plasma protein binding displacement can also

occur due to exogenously administered compounds such
as drugs.
• Other drugs that are highly bound to albumin and cause

plasma protein binding displacement drug interactions
with phenytoin include warfarin, valproic acid, aspirin (>2
g/d), and some highly bound nonsteroidal
antiinflammatory agents.
Basic Clinical Pharmacokinetic Parameters
• Phenytoin is primarily eliminated by hepatic
metabolism (>95%)mainly via the CYP2C9 enzyme
system with a smaller amount metabolized by
CYP2C19.
• Phenytoin follows Michaelis-Menten or saturable

pharmacokinetics
• In this case the rate of drug removal is described

by the classic Michaelis-Menten relationship that
is used for all enzyme systems:
rate of metabolism = (Vmax ⋅ C) / (Km + C)
Basic Clinical Pharmacokinetic Parameters
• Steady state is usually attained within 7–14 days but can take as
long as 28 days
• The clinical implication of Michaelis-Menten pharmacokinetics is

that the clearance of phenytoin is not a constant
Cl = Vmax / (Km + C)
• Phenytoin volume of distribution (V = 0.7 L/kg) is unaffected by

saturable metabolism and is still determined by the physiological
volume of blood
• t1/2. Phenytoin has no true half-life, but its apparent half-life

increases as serum level increases; at phenytoin serum levels of 1,
10, 20, and 40 mg/L, the predicted mean phenytoin half-lives are
13, 26, 40, and 69 hr, respectively.2,76
Time to Peak Cp
• Dose (mg) • Peak Time ( hrs)

• 400 • 8.4
• 800 • 13.2
• 1600 • 31.5
Parenteral Administration of
Phenytoin
Gugler R et al . Clin Pharmac.Ther 1976; 135-42

Conditions Affection Phenytoin
Condition or Example
Disease
Vmax increased Enzyme induction Concurrent
phenobarb/Carbaz
epine
Vmax decreased Cirrhosis Decreased
enzyme activity
Km increased Competitive Cimetidine or
Inhibition Chloramphenicol
Km decreased Decrease Dec. albumin or

ProteinBinding displacers:Valproi
c acid
Pharmacokinetic Dosing Method
• If the patient has significanthepatic dysfunction
(Child-Pugh score ≥8), maintenance doses
computed using this method should be
decreased by 25–50% depending on how
aggressive therapy is required to be for the
individual.
Michaelis-menten Parameter Estimates
• Normal adults with normal liver and renal function
as well as normal plasma protein binding have an
average phenytoin Vmax of 7 mg/kg/d and Km of
4 μg/mL.
• Michaelis-Menten parameters for younger

children (6 months–6 years) are Vmax = 12
mg/kg/d and Km = 6 μg/mL while for older
children (7–16 years) Vmax = 9 mg/kg/d and Km =
6 μg/mL.
VOLUME OF DISTRIBUTION ESTIMATE
• For obese individuals 30% or more above their
ideal body weight, the volume of distribution
can be estimated using the following
equation:
V = 0.7 L/kg [IBW + 1.33(TBW − IBW)]
• Loading Dose (in milligrams) for phenytoin

LD = Css ⋅ V
• Because of this, the Michaelis-Menten
pharmacokinetic equation that computes the
average phenytoin steady-state serum
concentration (Css in μg/mL = mg/L) is widely
used and allows maintenance dosage calculation:
MD = V . Css
S(Km + Css )
• S = fraction of the phenytoin salt form that is active phenytoin (0.92 for
phenytoin sodium injection and capsules)
• Km is the substrate concentration in mg/L (which equals μg/mL) where
the rate of metabolism = Vmax/2
Or
Css = Km . ( S . MD)
Vmax - ( S . MD)
CLEARENCE ESTIMATE
Cl = Vmax / (Km + C)
GRAVES-CLOYD METHOD
Dnew = (Dold / Cssold) ⋅ Cssnew0.199 ⋅ Cssold0.804
This dosage adjustment method uses a steady-state phenytoin serum

concentration to compute the patient’s own phenytoin clearance rate
Revised Winter-Tozer Equation for normalizing phenytoin levels for

hypoalbuminemic patients:
Cadjusted = Cmeasured
(0.25* [albumin]) + 0.1
Phenytoin Drug Interactions
•  [phenytoin] •  [phenytoin]
– carbamazepine
– diazepam – phenobarbital
– fluoxetine – valproic acid
– ethosuximide
– sucralfate
– salicylates
– Ca+2-containing antacids
– sulfonamides
– sucralfate
– H2RB’s
– chronic EtOH
– amiodarone
– phenothiazines
– trazodone
– INH
– estrogens
– acute EtOH
Phenytoin---Side Effects
• @ therapeutic levels
– nausea, vomiting, constipation
– gingival hyperplasia, hypertrichosis
– bone marrow suppression
– skin rashes (SJS, TEN are life-threatening)
– osteomalacia
– drug fever
– hepatotoxicity, hypothyroidism (rare)
• @ TOXIC levels (> 20-25 mg/L):

– ataxia, nystagmus, delirium, psychoses, slurred speech,
dizziness, seizures, coma, death
THE END

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CLINICAL PHARMACOKINETIC

Rahmad Abdillah., M.Si, Apt

• It is an effective anticonvulsant for the chronic treatment

• The antiseizure activity of phenytoin is related to its

• At total phenytoin concentrations above 20 μg/mL, nystagmus

• When total concentrations exceed 30 μg/mL, ataxia, slurred

• Phenytoin plasma protein binding displacement can also

• Other drugs that are highly bound to albumin and cause

• Phenytoin follows Michaelis-Menten or saturable

• In this case the rate of drug removal is described

• The clinical implication of Michaelis-Menten pharmacokinetics is

• Phenytoin volume of distribution (V = 0.7 L/kg) is unaffected by

• t1/2. Phenytoin has no true half-life, but its apparent half-life

• Dose (mg) • Peak Time ( hrs)

Gugler R et al . Clin Pharmac.Ther 1976; 135-42

Km decreased Decrease Dec. albumin or

• Michaelis-Menten parameters for younger

• Loading Dose (in milligrams) for phenytoin

This dosage adjustment method uses a steady-state phenytoin serum

Revised Winter-Tozer Equation for normalizing phenytoin levels for

• @ TOXIC levels (> 20-25 mg/L):

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