A drug with Michaelis-Menten (zero-order at therapeutic doses) kinetics shows disproportionate toxicity when the dose is increased by 20%. This is because at saturation kinetics:

• A Distribution volume increases exponentially with dose as drug saturates plasma protein binding sites
• B A small dose increase causes a disproportionately large rise in plasma concentration since elimination rate is fixed and cannot increase ✓
• C Bioavailability increases non-linearly due to saturation of first-pass metabolism increasing oral F significantly
• D Half-life increases proportionally with dose as the apparent Vd increases with plasma concentration

Explanation

At saturated elimination (zero-order kinetics), the metabolic enzyme (typically CYP, e.g., CYP2C9 for phenytoin) is working at maximum velocity (Vmax). The elimination rate is therefore constant (fixed amount per unit time) regardless of plasma concentration. Any increase in dose cannot be matched by a proportional increase in elimination, so plasma concentration rises precipitously and disproportionately. This explains phenytoin toxicity: the therapeutic window is narrow and a 20% dose increase can shift plasma levels from therapeutic to toxic because the 'no reserve' elimination capacity cannot compensate. Protein binding saturation causes non-linear distribution (increased free fraction) but this is a separate phenomenon.

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

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Written and medically reviewed by the StethoPrep medical team.