A drug demonstrates 'saturation kinetics' at therapeutic plasma concentrations. A patient is stabilized on phenytoin 300 mg/day with a plasma level of 12 mg/L. The dose is increased by only 50 mg/day to 350 mg/day. Two weeks later, the patient presents with diplopia, ataxia, and nystagmus. Plasma phenytoin level is 38 mg/L. What explains this disproportionate rise?

• A Phenytoin obeys first-order kinetics but the patient has developed CYP2C9 polymorphism, reducing metabolism
• B Phenytoin auto-inhibits its own metabolism via product inhibition; higher doses accelerate this inhibition catastrophically
• C Phenytoin obeys Michaelis-Menten (zero-order, saturable) kinetics; at therapeutic concentrations, hepatic CYP2C9/CYP2C19 are operating near maximum velocity (Vmax); a small dose increment overwhelms the saturated enzyme, causing disproportionate accumulation and toxicity ✓
• D Phenytoin has a large volume of distribution; the additional 50 mg fills the volume of distribution suddenly, causing toxicity

Explanation

Phenytoin is the classic example of a drug with capacity-limited (Michaelis-Menten, saturable, zero-order at high concentrations) pharmacokinetics. At subtherapeutic concentrations, phenytoin follows first-order kinetics (a constant fraction is eliminated per unit time). But at therapeutic concentrations (10-20 mg/L), the hepatic enzymes responsible (CYP2C9 primarily, CYP2C19 secondarily) are operating close to their maximum velocity (Vmax). Near saturation, adding even a small increment to the dose overwhelms the saturated enzyme's capacity, and elimination shifts decisively to zero-order kinetics (a constant amount — not fraction — eliminated per unit time). The dose eliminated per day plateaus while input exceeds elimination, causing progressive accumulation. This explains why doubling a 300 mg dose does not double plasma levels — it can cause exponential concentration increases and toxicity. Small incremental dose increases (25-50 mg) with level monitoring are required when titrating phenytoin.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.