Medservatory
USMLE Step 1Pharmacology: principles and autonomic drugsEP 07 of 16

Zero-order vs first-order elimination explained

First-order elimination removes a constant fraction per unit time; zero-order removes a constant amount. Saturation of metabolizing enzymes turns one into the other.

  • 5:12 video
  • 3 min read
  • 7 sources
  • Published 15 Nov 2026
Video lesson · 5:12 · Watch on YouTubeSeries: Pharmacology: Pharmacokinetics & Autonomic Drugs · @medservatory
Chapters (9)
By the end of this lesson

Distinguish zero-order (constant amount per time, saturated enzymes, no fixed half-life) from first-order (constant fraction per time) elimination kinetics, and name the drugs that saturate: phenytoin, ethanol and aspirin at toxic doses.

The short version

  1. First-order elimination removes a constant fraction of the drug per unit time, with a fixed half-life.
  2. Zero-order elimination removes a constant amount per unit time, whatever the concentration, with no fixed half-life.
  3. Saturation of the metabolizing enzymes turns first-order into zero-order.
  4. Near saturation, a small rise in dose can cause a disproportionately large rise in concentration.
  5. Phenytoin, ethanol and aspirin at toxic doses are the drugs to remember.

The case: a third more phenytoin, a much higher level

A man's seizures are controlled on 300 mg of phenytoin a day. His dose is raised by a third, to 400 mg. Weeks later he is unsteady, with jerking eyes, and his phenytoin level is far more than a third higher.[1]

The explanation is the difference between zero-order vs first-order elimination. Last lesson treated elimination as first-order, the usual case. Here the elimination pathway fills up, and the rules change.[1][2]

First-order elimination: a constant fraction per unit time

In first-order elimination, a constant fraction of the drug is eliminated per unit time. The rate rises and falls in proportion to the concentration, and the half-life stays fixed.[2][4]

It works because the enzymes and clearance mechanisms are running well below capacity, so more drug simply means more removal. At therapeutic concentrations of most drugs only a small fraction of the metabolizing enzyme sites is occupied.[2][4]

First-order: 600 mg in the body, half-life 2 hours
  1. After 2 hours: 600 → 300 mg
  2. After 4 hours: 300 → 150 mg
  3. After 6 hours: 150 → 75 mg
  4. Each interval removes half of what is left

Zero-order elimination: a constant amount, saturated enzymes

In zero-order elimination, a constant amount of the drug is eliminated per unit time, whatever the concentration.[2][4]

The cause is saturation. Almost all of the enzyme sites are occupied, so metabolism runs at its maximum rate. As the concentration rises, metabolism shifts from first-order to zero-order.[4]

Zero-order: the same 600 mg, enzymes saturated at 40 mg/h
  1. After 1 hour: 600 − 40 = 560 mg
  2. After 2 hours: 560 − 40 = 520 mg
  3. After 3 hours: 520 − 40 = 480 mg
  4. A straight line down

There is no fixed half-life here, because the time to halve depends on how much drug is present. The term becomes meaningless; one talks instead of the amount removed per unit time.[3][4]

First-order vs zero-order elimination side by side

Zero-order vs first-order elimination
FeatureFirst-orderZero-order
What is removed per unit timeA constant fractionA constant amount
Rate of eliminationProportional to the concentrationFixed, whatever the concentration
Half-lifeFixedNone fixed
EnzymesWorking well below capacitySaturated, at maximum rate
Amount left (600 mg example)300, 150, 75 mg at 2, 4, 6 hours560, 520, 480 mg at 1, 2, 3 hours: a straight line

Michaelis-Menten kinetics: the rate against concentration

Picture the rate of elimination against concentration. First-order is a rising straight line. Zero-order is a flat line at the maximum rate.[2]

Enzyme-mediated elimination combines them: first-order at low concentrations, then a curve that levels off at Vmax, when every enzyme is busy. That is Michaelis-Menten kinetics: first-order when low, zero-order when high.[2][4]

Why a small dose rise causes a large level rise

Once the enzymes are near their limit, the body cannot remove much more per hour, so a small rise in dose can cause a disproportionately large rise in concentration.[1][2]

That is the opening patient. A third more phenytoin, and the level climbs much further. Phenytoin metabolism is saturable, so levels rise dramatically with only a slight increase in daily dose.[1]

Drugs that saturate: phenytoin, ethanol, aspirin

Three drugs to remember
DrugElimination kinetics
PhenytoinSaturable metabolism; levels rise dramatically with only a slight increase in daily dose[1]
EthanolA roughly constant amount per hour, at all but very low blood levels[5]
AspirinFirst-order at normal doses; in overdose the pathway saturates and it becomes zero-order[6][7]

That is why phenytoin needs careful dosing with level monitoring, and why ethanol and salicylate levels in poisoning cannot be predicted from a fixed half-life.[1][3]

Practice question

Original · USMLE style
Your turnQB-MS-S1-PHARM-011-01

A 34-year-old man is brought to the emergency department after heavy drinking that ended before arrival. His blood ethanol concentration is 330 mg/dL on arrival, 210 mg/dL at 6 hours and 90 mg/dL at 12 hours.

Which of the following best describes the elimination of ethanol in this patient?
Pick one option. Your answers stay on this device.

Common questions

What is the difference between zero-order and first-order elimination?

First-order elimination removes a constant fraction of the drug per unit time. Zero-order elimination removes a constant amount per unit time, whatever the concentration.

Why does zero-order elimination have no fixed half-life?

The time to halve depends on how much drug is present, so there is no fixed half-life. In first-order elimination the half-life stays fixed.

What causes zero-order elimination?

Saturation. Almost all of the enzyme sites are occupied, so metabolism runs at its maximum rate, and the elimination shifts from first-order to zero-order.

Which drugs follow zero-order kinetics?

Phenytoin has saturable metabolism, ethanol is eliminated at a roughly constant amount per hour, and aspirin becomes zero-order in overdose when its pathway saturates.

Why does a small phenytoin dose increase cause a large rise in level?

Near saturation, a small rise in dose can cause a disproportionately large rise in concentration, because the enzymes cannot remove much more per hour.

Transcript

Read the full narration, by chapter627 words

0:00The case: phenytoin 300 to 400 mg, and a level far higher

A man's seizures are controlled on 300 milligrams of phenytoin a day. His doctor raises the dose by a third, to 400. Weeks later he is unsteady, with jerking eyes, and his phenytoin level is far more than a third higher. Why? Today: tell zero-order from first-order elimination, and name the drugs that saturate. Last time we treated elimination as first-order,

0:23First-order elimination: a constant fraction, a fixed half-life

the usual case. In first-order elimination, a constant fraction of the drug is eliminated per unit time. The rate rises and falls in proportion to the concentration, and the half-life stays fixed. Take 600 milligrams in the body with a half-life of 2 hours. After 2 hours, 300 remain. After four, 150. After six, 75. It works because the enzymes and clearance mechanisms are running well below capacity, so more drug simply means more removal.

1:01Zero-order elimination: saturated enzymes, a constant amount

In zero-order elimination, a constant amount of the drug is eliminated per unit time, whatever the concentration. The cause is saturation. Almost all of the enzyme sites are occupied, so metabolism runs at its maximum rate. Take the same 600 milligrams, but with the enzymes saturated at 40 milligrams per hour. After 1 hour, 560 remain. After two, 520. After three, 480. A straight line down. There is no fixed half-life here, because the time to halve depends on how much drug is present.

1:41Rate of elimination against concentration: Michaelis-Menten

Now picture the rate of elimination against concentration. First-order is a rising straight line. Zero-order is a flat line at the maximum rate. Real drugs combine them: first-order at low concentrations, then a curve that levels off at V max, when every enzyme is busy. That is Michaelis-Menten kinetics: first-order when low, zero-order when high.

2:06A steep dose response: why the level jumps

The consequence is a steep dose response. Once the enzymes are near their limit, a small rise in dose can cause a disproportionately large rise in concentration. That is our patient. A third more phenytoin, and the level climbs much further.

2:23Three drugs: phenytoin, ethanol, aspirin at toxic doses

Three drugs to remember: phenytoin, ethanol, and aspirin at toxic doses. Phenytoin's metabolism is saturable, so levels rise dramatically with only a slight increase in daily dose. Ethanol is eliminated at a roughly constant amount per hour, at all but very low blood levels. Aspirin follows first-order kinetics at normal doses, but in overdose the pathway saturates and it becomes zero-order. That is why these drugs need careful dosing or level monitoring.

2:56Practice question: ethanol levels over 12 hours

Your turn. A 34-year-old man is brought to the emergency department after heavy drinking that ended before he arrived. His blood ethanol concentration is 330 milligrams per decilitre on arrival, 210 at 6 hours, and 90 at 12 hours. Which of the following best describes the elimination of ethanol in this patient? A, first-order kinetics; metabolizing enzymes working well below capacity. B, zero-order kinetics; metabolizing enzymes saturated. C, first-order kinetics; metabolizing enzymes saturated. D, zero-order kinetics; metabolizing enzymes working well below capacity. E, neither; the fall reflects redistribution into tissues, not elimination. Pause here and decide.

3:54Answer and explanation

A is out: first-order elimination removes a constant fraction, but here the falls are 120 then 120, which is 36%, then 57. C is out: saturated enzymes remove a fixed amount, not a fraction, so first-order cannot go with saturation. D is out: enzymes working below capacity give first-order, not zero-order, kinetics. E is out: ethanol distributes through total body water, so a steady fall over 12 hours reflects elimination, not redistribution. So the answer is B. The concentration falls by the same amount each interval, which is zero-order kinetics from saturated enzymes.

4:41Recap and next lesson

Three things to keep. One: first-order removes a constant fraction, with a fixed half-life. Zero-order removes a constant amount, with no fixed half-life. Two: saturation turns first-order into zero-order, so small dose rises cause big level rises. Three: phenytoin, ethanol and aspirin at toxic doses. Next, loading and maintenance doses.

Sources

Numbers in the text, e.g. [1], point here
  1. LITFL. Phenytoin toxicity. litfl.com/phenytoin-toxicity/
  2. Deranged Physiology. First order, zero order and non-linear elimination kinetics. derangedphysiology.com/main/cicm-primary-exam/pharmacokinetics/Chapter-337/first-order-zero-order-and-non-linear-elimination-kinetics
  3. Deranged Physiology. Half-life. derangedphysiology.com/main/cicm-primary-exam/pharmacokinetics/Chapter-322/half-life
  4. MSD Manual Professional Version. Drug Metabolism. msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism
  5. LITFL. Ethanol toxicity. litfl.com/ethanol-toxicity/
  6. LITFL. Salicylate toxicity. litfl.com/salicylate-toxicity/
  7. Europe PMC. europepmc.org/article/PMC/PMC11351987 · europepmc.org/article/PMC/PMC12414438 · europepmc.org/article/MED/33099270

The doses, amounts and ethanol levels on screen are teaching values written for this lesson. The two "time to halve" figures on the zero-order graph are simple arithmetic from them: 300 mg ÷ 40 mg/h = 7.5 h and 150 mg ÷ 40 mg/h = 3.75 h.

The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.

Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): man, eye, enzymes, liver. Drug bottle icon by Servier via Bioicons (bioicons.com), CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/), adapted. Pill icon by Marcel Tisch via Bioicons, CC0. Alcohol and hospital bed icons: Health Icons (healthicons.org), CC0. The graphs, dots, gauge, cards and all handwriting are drawn in code (original). No AI-generated teaching images.

Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-PHARM-011.

For exam study only, not medical advice. Read the medical disclaimer.

In this series

Playlist on YouTube
← Previous · EP 06Clearance and half-life: t½ = 0.693 × Vd / CL
  1. EP 01Potency vs efficacy: EC50, Emax and agonist types5:17
  2. EP 02Competitive vs noncompetitive antagonists: effect on EC50 and Emax5:01
  3. EP 03Therapeutic index explained: TD50 / ED505:01
  4. EP 04First-pass metabolism and bioavailability: calculating oral F from AUC5:18
  5. EP 05Volume of distribution: why Vd can be bigger than the body5:17
  6. EP 06Clearance and half-life: t½ = 0.693 × Vd / CL5:01
  7. EP 07Zero-order vs first-order elimination explained5:12
  8. EP 08Loading dose and maintenance dose, explained5:02
  9. EP 09CYP450 inducers and inhibitors: how they change drug levels5:16
  10. EP 10Autonomic receptors: alpha, beta and muscarinic5:33
  11. EP 11Beta blocker selectivity: beta-1, ISA and alpha blockade5:24
  12. EP 12Vasopressors compared: receptors, pressure and heart rate5:46
  13. EP 13Organophosphate poisoning: muscarinic vs nicotinic signs5:36
  14. EP 14Receptor desensitization, downregulation and upregulation5:01
  15. EP 15Beta-lactams and vancomycin: enzyme versus substrate5:04
  16. EP 16Protein synthesis inhibitors: 30S vs 50S antibiotics5:07