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Pharmacology · Statins

Simvastatin !

An older, widely used statin swallowed as an inactive lactone that the liver turns into the active drug; prone to CYP3A4 interactions.

Updated 2026-11-01

  • Class: Statins
  • Enzyme: HMG-CoA reductase
  • ATC code: C10AA01
  • WHO Model List of Essential Medicines

The crystal holds simvastatin acid, the active open-ring form, not the lactone that is swallowed.

Target in 3D: HMG-CoA reductase. PDB structure 1HW9 (RCSB PDB, public domain). View the structure at RCSB PDB

Mechanism of action

Simvastatin is a lactone prodrug that is hydrolysed to its active beta-hydroxyacid, which competitively inhibits HMG-CoA reductase. Lower intracellular cholesterol raises LDL receptor numbers through SREBP-2, and the liver clears more LDL from the blood. Its label directs once-daily evening dosing.

  1. The lactone prodrug opens to simvastatin acid in the liver
  2. The acid blocks HMG-CoA reductase: less mevalonate
  3. Liver cells add LDL receptors (SREBP-2)
  4. LDL falls and atherosclerotic events drop

Pharmacokinetics

Absorption
Oral; extensive first-pass extraction by the liver leaves less than 5% in the general circulation.
Distribution
About 95% bound to plasma proteins, with the active acid.
Metabolism
Hydrolysed to the active acid; metabolized by CYP3A4.
Elimination
About 60% in feces and 13% in urine.

Indications

Adverse effects

Common

  • Muscle aches (myalgia)
  • Raised liver transaminases
  • Constipation, abdominal pain, nausea
  • Small rise in new-onset type 2 diabetes in predisposed people

Contraindications

  • Strong CYP3A4 inhibitors (azole antifungals, macrolide antibiotics, some antivirals, nefazodone)
  • Cyclosporine, danazol or gemfibrozil
  • Acute liver failure or decompensated cirrhosis
  • Hypersensitivity to simvastatin; it is stopped when pregnancy is recognized

Key interactions

Strong CYP3A4 inhibitors (azole antifungals, macrolides such as clarithromycin, HIV protease inhibitors)
Large rise in simvastatin levels and in the risk of rhabdomyolysis; contraindicated.
Gemfibrozil, cyclosporine and danazol
Raise the risk of myopathy; contraindicated.
Verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine
Raise simvastatin levels, so lower maximum doses apply.
Grapefruit juice
Raises plasma levels and the risk of myopathy; it is avoided.

What is monitored

  • Lipid panel before starting and some weeks later
  • Liver enzymes at baseline
  • Creatine kinase if there are muscle symptoms

Test yourself

Think of the answer, then tap the question to see it.

What does it mean that simvastatin is a prodrug?

It is swallowed as an inactive lactone; hydrolysis, largely in the liver, opens the ring to simvastatin acid, the form that inhibits HMG-CoA reductase.

Why does so little simvastatin reach the general circulation, and why is that acceptable?

The liver extracts most of it on first pass, leaving less than 5% in the circulation; the liver is where it inhibits cholesterol synthesis.

Why are simvastatin doses capped in patients who also take amlodipine or amiodarone?

Both drugs raise simvastatin levels by inhibiting its metabolism, which increases the risk of myopathy.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Simvastatin: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); DailyMed - SIMVASTATIN- simvastatin tablet, film coated (DailyMed (U.S. National Library of Medicine), 2026); COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH SIMVASTATIN (RCSB Protein Data Bank, 2001); eEML - Electronic Essential Medicines List (World Health Organization, 2025).

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Representative model, for educational purposes only.