The phenomenon of 'zero-order kinetics' in phenytoin toxicity occurs because:

• A Phenytoin undergoes renal tubular secretion that becomes saturated above therapeutic concentrations
• B Phenytoin is metabolised by CYP2C9/2C19, which become saturated at therapeutic plasma concentrations ✓
• C Phenytoin forms inactive glucuronide conjugates that accumulate in renal failure
• D Phenytoin binds to plasma albumin non-linearly at high concentrations

Explanation

Phenytoin is metabolised primarily by CYP2C9 (and to a lesser extent CYP2C19) via hydroxylation to inactive HPPH (p-hydroxyphenyl derivative). This metabolic pathway becomes saturated (exhibits Michaelis-Menten kinetics) at plasma concentrations within the therapeutic range (~10-20 mcg/mL). Once enzymes are saturated, a fixed amount of drug (not a fixed fraction) is eliminated per unit time — zero-order kinetics — meaning small dose increases cause disproportionately large plasma concentration rises. This narrow therapeutic index requires careful titration.

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

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Written and medically reviewed by the StethoPrep medical team.