DrugTheGuide
Pharmacokinetics

Zero-order kinetics

A drug elimination process where the rate is constant and independent of concentration — because the metabolic pathway is saturated. Contrast with first-order kinetics.

Zero order kinetics occurs when the enzyme system responsible for drug elimination becomes saturated — operating at maximum velocity (Vmax) regardless of how much drug is present. Under these conditions, a constant amount (not fraction) of drug is eliminated per unit time, producing a linear rather than exponential decline in plasma concentration. The most clinically important examples of zero order kinetics are phenytoin (DailyMed) ↗ (CYP2C9 saturation within the therapeutic range), ethanol (NCBI) ↗ (alcohol dehydrogenase saturation at typical drinking concentrations, eliminating ~10–15 mL/h regardless of blood alcohol level), and high-dose aspirin (glycine conjugation pathway saturation above ~1 g/day). For phenytoin, this saturation kinetics means that small dose increases near the enzyme's Km can cause disproportionately large — and potentially toxic — rises in plasma concentration, making it a classic narrow therapeutic index drug. The WHO Model Formulary ↗ and Medscape ↗ flag zero-order drugs for special dosing precautions.

PharmacokineticsSaturable eliminationMichaelis-MentenPhenytoin

Key equations

Zero-order rate equation
dC/dt = −k₀
Rate constant k₀ has units of concentration/time (e.g., mg/L/h); independent of C
Plasma concentration over time
C(t) = C₀ − k₀ × t
Linear decline — plot of C vs t is a straight line (not curved like first-order)
Michaelis-Menten equation
Rate = Vmax × C / (Km + C)
Vmax = maximum rate; Km = concentration at half-maximum rate; C = plasma concentration
No constant half-life
t½ = C₀ / (2 × k₀)
Half-life increases as concentration rises — no fixed t½ unlike first-order kinetics

Zero-order vs first-order kinetics

PropertyZero-orderFirst-order
Elimination rateConstant (fixed amount/time)Proportional to concentration (fixed fraction/time)
Plasma-time curveLinearExponential (log-linear)
Half-lifeVariable — increases as C risesConstant
Dose proportionalityNon-linear — AUC increases disproportionately with doseLinear — AUC proportional to dose
CauseSaturated enzyme/transporterUnsaturated elimination at therapeutic doses
Time to steady stateUnpredictable — depends on dose relative to Km5 × t½ (predictable)
Clinical examplesPhenytoin, ethanol, high-dose aspirin, fluorouracilMost drugs (ibuprofen, metformin, warfarin, most antibiotics)

Clinical examples with saturable kinetics

Phenytoin (fosphenytoin)

CYP2C9 is saturated within the therapeutic range (10–20 mg/L). Near-saturation means dose escalation produces unpredictable large plasma level rises. DailyMed phenytoin ↗. Increase by ≤50 mg/day steps; monitor TDM.

Ethanol

Alcohol dehydrogenase saturated at drinking concentrations → linear BAC decline (~10–15 mL/h). CYP2E1 induction with chronic use adds first-order component. NCBI StatPearls ↗.

Aspirin (high-dose)

At anti-inflammatory doses (≥2 g/day), glycine conjugation (salicylate pathway) becomes saturated → zero-order kinetics develop. At analgesic/antipyretic doses (<1 g), first-order elimination predominates.

Fluorouracil (5-FU)

Dihydropyrimidine dehydrogenase (DPD) is the primary inactivation enzyme; high-dose bolus 5-FU can saturate DPD. DPD deficiency (DPYD gene polymorphisms) further shifts kinetics and increases toxicity risk. See pharmacogenomics guide.

Frequently asked questions

What is the difference between zero-order and first-order kinetics?
In first-order kinetics, a constant fraction is eliminated per unit time (exponential decline; half-life is constant). In zero-order kinetics, a constant amount is eliminated per unit time — because the metabolic enzymes (e.g., CYP2C9 for phenytoin ↗) are saturated. The plasma-time curve is linear rather than log-linear. See NCBI StatPearls pharmacokinetics ↗ for the mathematical derivation.
Which drugs follow zero-order (Michaelis-Menten) kinetics?
Clinical drugs showing zero-order/saturable kinetics: Phenytoin ↗ (CYP2C9 saturation — the classic example); ethanol (alcohol dehydrogenase saturation at typical drinking doses ~10 mg/h elimination); high-dose aspirin; fluorouracil. Phenytoin's saturability at therapeutic doses makes it a narrow TI drug — dose increases near the Km cause large plasma concentration rises. Related: therapeutic window.
What is the Michaelis-Menten equation in pharmacokinetics?
The Michaelis-Menten equation: Rate = Vmax × C / (Km + C). When C ≫ Km (saturation): Rate ≈ Vmax (constant, zero-order). When C ≪ Km: Rate ≈ (Vmax/Km) × C — proportional to C (first-order). Phenytoin's Km is ~5–10 mg/L — overlapping its therapeutic range (10–20 mg/L), meaning partial saturation occurs at therapeutic doses. Use the half-life calculator for first-order context; phenytoin requires the Michaelis-Menten form. See NCBI StatPearls ↗.
Why is zero-order kinetics dangerous for phenytoin dosing?
Because phenytoin operates near CYP2C9 saturation, small dose increases (e.g., 300 → 400 mg/day) produce disproportionately large plasma level rises. At concentrations above Km, accumulation is rapid and non-predictable. Standard linear dose escalation is dangerous. Practical guidance: increase phenytoin in steps of ≤50 mg/day and recheck levels after 2 weeks minimum. Use TDM and the Sheiner-Tozer equation for individualised target dose. See also: narrow therapeutic index.
How does ethanol follow zero-order kinetics?
Ethanol is metabolised by alcohol dehydrogenase (ADH) ↗, which has a very low Km (~0.1 g/L). At typical drinking concentrations (0.5–3 g/L), ADH is fully saturated → constant elimination ~10–15 mL ethanol/h (~one standard drink). The blood alcohol vs time plot is linear after peak — zero-order. At very low concentrations (post-clearance), first-order re-emerges. Drug interactions with CYP2E1 inducers/inhibitors (disulfiram, isoniazid) can significantly alter ethanol metabolism kinetics. See CYP450 guide.