A drug undergoes zero-order (saturable) kinetics when plasma concentrations exceed a threshold. Which clinical consequence distinguishes zero-order from first-order pharmacokinetics?

• A In zero-order kinetics, doubling the dose exactly doubles the plasma concentration at steady-state (proportional dose-response)
• B In zero-order kinetics, a fixed amount of drug is eliminated per unit time; small dose increases above the saturation threshold cause disproportionately large rises in plasma concentration ✓
• C Zero-order kinetics have a shorter half-life because enzyme saturation speeds up metabolism
• D Zero-order kinetics apply only to parenteral routes of administration

Explanation

First-order kinetics: a constant fraction of drug is eliminated per unit time (half-life is constant, plasma levels proportional to dose). Zero-order (saturable/Michaelis-Menten) kinetics: metabolising enzymes are saturated so a fixed absolute amount is eliminated per unit time regardless of concentration. At zero-order kinetics, even small dose increments above the saturating threshold cause disproportionate plasma concentration increases (non-linear PK), making toxicity risk unpredictable. Classic clinical examples: phenytoin, alcohol, aspirin at high doses, and heparin at very high concentrations — all subject to steep, dangerous dose-toxicity relationships.

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

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