Metamizol: the pathway in the body

Metamizol is part of the pathway “Metamizol”. This page shows the whole pathway; the station of Metamizol is highlighted.

Where this laboratory value sits: Metamizole — not yet the active form. Metamizole is swallowed and is not itself the form that acts. It belongs to the pyrazolones and is a prodrug — a precursor from which the active form arises only in the body. It does not act at the enzyme itself. Source 1, 2

In brief

Metamizole is a pyrazolone and not yet active itself. In the body it breaks down without an enzyme into 4-methylaminoantipyrine, which acts on the haem iron of cyclooxygenase. Described is a redirection of the formation rather than a full stop. Less PGE₂ then forms.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Metamizole → 4-Methylaminoantipyrine · Water Even before absorption, metamizole breaks down in water into 4-methylaminoantipyrine, MAA for short. This breakdown needs no enzyme; it runs by itself. Only MAA passes into the blood. MAA acts on the haem iron of cyclooxygenase. Source 1, 2↓ depletes MAA is the main form that acts: in cell experiments it acts on the haem iron of cyclooxygenase and redirects prostaglandin formation. The action lasts while MAA circulates in the blood. observed in studies Source 3, 1
   ⚖ When the balance tips

   too much — If a lot of MAA is present, a larger part of cyclooxygenase activity is damped; in cell experiments the formation of prostaglandin E₂ then falls markedly.

   too little — If little MAA is present, the haem iron stays mostly in the oxidised state, and cyclooxygenase continues to work largely unhindered.

   observed in studies · Source 3

2. 4-Methylaminoantipyrine → 4-Aminoantipyrine CYP2C19 In the liver CYP2C19 removes the methyl group from MAA; 4-aminoantipyrine (AA) arises. Another part of the MAA is converted into 4-formylaminoantipyrine, an end product. AA also binds the haem of cyclooxygenase. Source 1, 4↓ depletes AA also binds the haem of cyclooxygenase. Because it arises from MAA and is broken down only later, it carries the action on when MAA is already falling. observed in studies Source 3, 1
   ⚖ When the balance tips

   too much — If CYP2C19 works quickly, more AA forms from MAA; the action is then spread more onto this second active form.

   too little — If CYP2C19 works slowly, for instance with inherited variants, more MAA persists for longer, and less AA forms.

   observed in studies · Source 4

3. 4-Aminoantipyrine → 4-Acetylaminoantipyrine NAT2 · Acetyl-CoA N-acetyltransferase 2 attaches an acetyl group to AA; it comes from acetyl-CoA. How fast this step runs is laid down in the genes and differs from person to person. AAA no longer acts at the enzyme. Source 1, 4, 5↓ depletes With the acetyl group AA loses its action at the enzyme; AAA is an end product that is only excreted. NAT2 thus removes active form from the path. established physiology Source 1
   ⚖ When the balance tips

   too much — If NAT2 acetylates quickly, AA is rapidly converted into AAA; the blood then contains more AAA and less AA.

   too little — If NAT2 acetylates slowly, AA stays in the blood longer, and more of it is available at the haem of cyclooxygenase.

   observed in studies · Source 5, 4

4. 4-Acetylaminoantipyrine → Excretion The four breakdown products leave the body mostly in the urine. The unchanged parent substance is practically undetectable in the blood. This ends their action. Source 1↓ depletes Via the kidneys the breakdown products leave the body; this finally ends their action at the enzyme. established physiology Source 1
   ⚖ When the balance tips

   too much — If the kidneys excrete promptly, the breakdown products leave the body quickly, and their level in the blood falls correspondingly faster.

   too little — If the kidneys excrete more slowly, the breakdown products stay in the blood longer, because the urine is their main route out of the body.

   established physiology · Source 1

5. In the cell membrane → Free arachidonic acid cPLA2 · Calcium When calcium inside the cell rises, the phospholipase cPLA2 moves to the membrane and cuts arachidonic acid out. Only as a free molecule is it converted further. Without free fatty acid, cyclooxygenase rests. Source 7↑ supplies Free arachidonic acid is the starting material that cyclooxygenase needs. Without a stimulus and calcium hardly any is released, and the path rests. established physiology Source 7, 6
   ⚖ When the balance tips

   too much — If a lot of arachidonic acid is released, cyclooxygenase converts more of it, provided its haem iron is activated.

   too little — If little arachidonic acid is released, cyclooxygenase has no starting material, and hardly any prostaglandins form, even when the enzyme is ready to work.

   established physiology · Source 6, 7

6. Free arachidonic acid → PGH₂ COX-1 and COX-2 · Haem iron, Oxygen Cyclooxygenase adds oxygen and forms a ring; PGG₂ arises. The peroxidase part of the same enzyme, a haem with iron, turns it into PGH₂ — the precursor of the prostaglandins and of thromboxane. The cell decides the end product. Source 6, 3↑ supplies PGH₂ is short-lived and is passed on at once: which synthase a cell carries decides whether it becomes prostaglandin E₂, thromboxane A₂ or another prostanoid. established physiology Source 6, 8
   ⚖ When the balance tips

   too much — If a lot of PGH₂ forms, the downstream synthases convert more of it; where COX-2 and mPGES-1 are made together, as in inflamed tissue, mainly prostaglandin E₂ forms.

   too little — If little PGH₂ forms, all downstream synthases receive less starting material; prostaglandins and thromboxane decrease together.

   established physiology · Source 6, 8

7. PGH₂ → Prostaglandin E₂ PGE synthases · Glutathione Tissue-own synthases make the individual prostaglandins out of PGH₂. The microsomal PGE synthase-1 needs glutathione for this. It widens vessels and makes nerve endings more sensitive. Source 8↑ supplies Prostaglandin E₂ acts via EP receptors: it widens vessels, makes nerve endings more sensitive and raises the set point of body temperature in the brain. established physiology Source 8
   ⚖ When the balance tips

   too much — If a lot of prostaglandin E₂ is present, as with an inflammatory stimulus, nerve endings respond to weaker stimuli, and body temperature is set higher.

   too little — If little prostaglandin E₂ is present, nerve endings respond only to stronger stimuli, and the set point of body temperature stays at its baseline.

   established physiology · Source 8

8. PGH₂ → Thromboxane A₂ Thromboxane synthase In blood platelets the thromboxane synthase converts PGH₂ into thromboxane A₂. There this path runs via COX-1. It soon breaks down into inactive thromboxane B₂. Source 6↑ supplies Thromboxane A₂ makes platelets change shape and stick to one another, and it narrows vessels. It is short-lived and breaks down rapidly into inactive thromboxane B₂. established physiology Source 6
   ⚖ When the balance tips

   too much — If the platelets make a lot of thromboxane A₂, they draw in further platelets, and the vessels narrow more strongly at that site.

   too little — If the platelets make little thromboxane A₂, they stick together more slowly, and a small injury to the vessel wall closes more slowly.

   established physiology · Source 6

Further stations

• Metamizole — not yet the active form Metamizole is swallowed and is not itself the form that acts. It belongs to the pyrazolones and is a prodrug — a precursor from which the active form arises only in the body. It does not act at the enzyme itself. Source 1, 2↑ supplies Metamizole is the store from which the active forms arise: it breaks down rapidly and completely into MAA and does not itself act at the enzyme. established physiology Source 1, 2
  ⚖ When the balance tips

  too much — If a lot of metamizole arrives, a correspondingly large amount of MAA forms, because the breakdown runs without an enzyme and no enzyme capacity limits it.

  too little — If little metamizole arrives, little MAA forms, and cyclooxygenase remains largely unaffected; the parent substance itself does not act at the enzyme.

  established physiology · Source 1, 3

• Haem of cyclooxygenase — iron in the peroxidase part MAA and AA form firm complexes with the haem and turn its Fe³⁺ into Fe²⁺. They thereby act on the iron that starts the reaction of cyclooxygenase — not in the channel for the fatty acid. Without this starting step cyclooxygenase rests. Source 3, 6↑ supplies The haem iron in the peroxidase part starts the reaction: via a small amount of peroxide a radical forms, with which cyclooxygenase attacks arachidonic acid. established physiology Source 6
  ⚖ When the balance tips

  too much — If a lot of haem iron is activated, many cyclooxygenases start up, and plenty of PGG₂ and PGH₂ forms.

  too little — If MAA or AA put the haem iron into the Fe²⁺ state, the starting step fails in cell experiments; cyclooxygenase then converts less arachidonic acid.

  observed in studies · Source 3, 6

• In the cell membrane — arachidonic acid built in Arachidonic acid lies mostly in the phospholipids of the cell membranes, usually at the middle position of the glycerol backbone. It stays there until a stimulus reaches the cell. The membrane is its store. Source 7↑ supplies The membrane is the store: only a stimulus makes arachidonic acid available to cyclooxygenase. It is formed from linoleic acid, or it comes directly from food. established physiology Source 7, 9
  ⚖ When the balance tips

  too much — If there is a lot of arachidonic acid in the membranes, a stimulus can release a correspondingly large amount; more starting material is then available to cyclooxygenase.

  too little — If there is little arachidonic acid in the membranes, less is released upon a stimulus, and the formation of prostaglandins and thromboxane stays low.

  established physiology · Source 7

What this active substance affects

• Iron — The active breakdown products bind the haem of cyclooxygenase and turn its Fe³⁺ into Fe²⁺; starts the reaction Source 3, 6
• Arachidonic acid — Starting material of cyclooxygenase; via PGH₂ it gives rise to the prostaglandins and to thromboxane Source 6, 7

What takes part in these steps

• Calcium — When it rises inside the cell, the phospholipase cPLA2 moves to the membrane and frees arachidonic acid; starts the path Source 7
• Glutathione — The microsomal PGE synthase-1 needs glutathione to convert PGH₂ into prostaglandin E₂; without it, less PGE₂ forms Source 8
• Linoleic acid — Omega-6 fatty acid from food, from which arachidonic acid arises over several steps; stock for the membrane Source 9
• Acetyl-CoA — Supplies N-acetyltransferase 2 with the acetyl group it attaches to 4-aminoantipyrine; AAA no longer acts at the enzyme Source 5, 1

What a review brings together

There is no US prescribing information for metamizole: the substance is not approved as a medicine in the United States, and DailyMed lists it only as a raw material. The figures therefore come from a systematic review with meta-analysis — 79 trials with almost 4,000 adults who each received the substance for less than two weeks. That review does not count individual complaints; it only compares how often adverse events were reported in total.

How to read the table: it counts no individual complaints but compares groups. Each row states what the comparison was against and how it turned out. There is therefore no separate column for a placebo — the placebo is a row here. And “no difference found” does not mean “no difference present”: with this number of participants, rare events stay invisible.

The review records that the trials assessed were mostly short and the reports of mediocre quality; for longer use, informative trials are missing. As the most severe reaction described, the reviews name agranulocytosis, a steep fall in certain white blood cells. It did not occur in the trials assessed; how common it is cannot be derived from this.

Sources

1. Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet 1995 · PubMed 7758252
2. Jasiecka A, Maślanka T, Jaroszewski JJ. Pharmacological characteristics of metamizole. Pol J Vet Sci 2014 · PubMed 24724493
3. Pierre SC, Schmidt R et al. Inhibition of cyclooxygenases by dipyrone. Br J Pharmacol 2007 · PubMed 17435797
4. Martínez C, Andreu I et al. Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole. Biochem Pharmacol 2014 · PubMed 25241292
5. Hein DW, Millner LM. Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review. Expert Opin Drug Metab Toxicol 2021 · PubMed 33094670
6. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 2000 · PubMed 10966456
7. Leslie CC. Regulation of the specific release of arachidonic acid by cytosolic phospholipase A2. Prostaglandins Leukot Essent Fatty Acids 2004 · PubMed 15041029
8. Samuelsson B, Morgenstern R, Jakobsson PJ. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 2007 · PubMed 17878511
9. Brenna JT, Kothapalli KSD. New understandings of the pathway of long-chain polyunsaturated fatty acid biosynthesis. Curr Opin Clin Nutr Metab Care 2022 · PubMed 34937850
10. Kötter T, da Costa BR et al. Metamizole-associated adverse events: a systematic review and meta-analysis. PLoS One 2015 · PubMed 25875821

Whole pathway: Metamizol

Related pathways

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As of 2026-09-25. Draft, written by Claude to schema v2; sources checked in PubMed; expert approval pending
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