Step 1: What is non-linear pharmacokinetics?
When pharmacokinetic parameters (like clearance or half-life) change with dose or concentration, the drug shows non-linear (dose-dependent) kinetics. There are several possible causes.
Step 2: Phenytoin's unique behaviour.
Phenytoin is the classic example of a drug with saturable metabolism. It is metabolised mainly by CYP2C9 enzymes. At low doses, plenty of enzyme is available and kinetics appear first-order. But as the dose increases, the enzymes become saturated and elimination shifts toward zero-order (Michaelis-Menten kinetics). A small dose increase can cause a disproportionately large rise in plasma concentration, making dosing dangerous.
Step 3: Eliminate the other causes.
Enzyme induction would increase metabolism and reduce levels, not cause non-linearity. Saturation of plasma protein binding does cause non-linearity but is not the primary reason for phenytoin's non-linearity. Saturation of renal excretion is not a significant feature of phenytoin (it is mainly hepatically metabolised).
Step 4: Clinical importance.
Because of saturable metabolism, phenytoin requires careful therapeutic drug monitoring. Even small dose increments near the therapeutic range can push levels into the toxic range.
Step 5: Conclusion.
The non-linearity of phenytoin is due to saturation of its metabolic enzymes (CYP2C9), giving it Michaelis-Menten kinetics.
Answer: Option (2) — Saturation of metabolic enzymes