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Simvastatin Pathway, Pharmacokinetics

PA166254341 Last updated August 2024 Caroline F. Thorn & Li Gong
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Drugs & chemicals
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Conditions
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Reactions
Simvastatin Pathway, Pharmacokinetics pathway diagram
Simvastatin Pathway, Pharmacokinetics — pathway diagram from PharmGKB / ClinPGx
Click to enlarge

About this pathway

Background

Simvastatin is an HMG-CoA reductase inhibitor (statin) used to lower the blood levels of low-density lipoprotein (LDL) and total cholesterol, indicated for the treatment of hyperlipidemia, reduction in risk of cardiovascular events and mortality of coronary heart disease patients. Simvastatin inhibits endogenous cholesterol production by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the enzyme that catalyzes conversion of HMG-CoA to mevalonate depicted in the Statin Pathway, Pharmacodynamics. .

Guidelines regarding the use of pharmacogenomic information in dosing for simvastatin were published by drug label and professional societies such as Clinical Pharmacogenetic Implementation Consortium, CPIC, and the Dutch Pharmacogenetics Working Group, DPWG. Given the strong evidence linking statin-induced myopathy and SLCO1B1 genotype, both CPIC and DPWG recommends alternative statin for patients with SLCO1B1 rs4149056 CC or TC genotype, or patients with SLCO1B1 decreased function or poor function phenotype.

Metabolism

Simvastatin is administered as an inactive lactone, and hydrolyzed to the active simvastatin acid by carboxyesterase and paraoxonase such as CES1 and PON1 [Articles:34045219, 31172248]. Simvastatin acid is a potent inhibitor of HMG-CoA reductase. Simvastatin acid can also be converted back to simvastatin via glucuronidation catalyzed by UGT1A1 or UGT1A3 [Article:34045219], [Article:11950779]. Both simvastatin and simvastatin acid are extensively metabolized by CYP3A4/5 to form 3-hydroxysimvastatin and 6-hydroxymethyl-simvastatin and -simvastatin acid [Articles:34045219, 9321523, 31172248].

Transport

Simvastatin is a substrate of the transport protein OATP1B1 (encoded by gene SLCO1B1) [Articles:15564882, 15970799, 34045219]. Simvastatin transported may also be affected by efflux transporters ABCB1 and ABCC2 [Articles:30024814, 22186618, 19238649, 16321621]. Genetic variation in SLCO1B1 rs4149056 (c.521T>C) has been reported to markedly increase systemic exposure of simvastatin acid [Articles:17108811, 23469684], [Article:31172248], [Article:29469964], [Article:26164721] and has been identified repeatedly as a risk factor for statin-induced muscle toxicity [Articles:21243006, 18650507, 31220337, 29242847, 30250148].

Reactions & interactions (32)

  • Biochemical Reaction
    simvastatin acid → simvastatin acyl glucuronide
  • Biochemical Reaction
    6-exomethylenesimvastatin → 6-hydroxymethyl simvastatin
  • Biochemical Reaction
    simvastatin → simvastatin acid
  • Biochemical Reaction
    simvastatin acyl glucuronide → simvastatin
  • Biochemical Reaction
    simvastatin → 3,5-dihydrodiol simvastatin
  • Biochemical Reaction
    6-exomethylenesimvastatin → 6'-carboxy simvastatin
  • Biochemical Reaction
    simvastatin → 6-exomethylenesimvastatin
  • Biochemical Reaction
    simvastatin acid → 6-hydroxymethyl simvastatin acid
  • Biochemical Reaction
    simvastatin → simvastatin acid
  • Biochemical Reaction
    simvastatin → 3'-hydroxysimvastatin
  • Catalysis
    UGT1A1 → Biochemical Reaction
  • Catalysis
    UGT1A3 → Biochemical Reaction
  • Catalysis
    CES1 → Biochemical Reaction
  • Catalysis
    PON1 → Biochemical Reaction
  • Catalysis
    ABCB1 → Transport
  • Catalysis
    ABCC2 → Transport
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Catalysis
    SLCO1B1 → Transport
  • Catalysis
    CYP3A5 → Biochemical Reaction
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Catalysis
    CYP3A5 → Biochemical Reaction
  • Catalysis
    CYP2C8 → Biochemical Reaction
  • Catalysis
    PON1 → Biochemical Reaction
  • Catalysis
    CES1 → Biochemical Reaction
  • Catalysis
    CYP3A4 → Biochemical Reaction
  • Inhibition
    6-exomethylenesimvastatin → HMGCR
  • Inhibition
    6'-carboxy simvastatin → HMGCR
  • Inhibition
    6-hydroxymethyl simvastatin acid → HMGCR
  • Inhibition
    simvastatin acid → HMGCR
  • Transport
    simvastatin → simvastatin
  • Transport
    simvastatin → simvastatin

Edit history (5)

  • 2021-11-01 Create
  • 2022-02-03 Update Updated image and image map.
  • 2022-02-20 Update Pathway updated to be specific for simvastatin and its metabolites, new gpml, new figure and text.
  • 2022-02-20 Update Linked related statin pathways.
  • 2024-08-30 Update Removed CYP3A from gpml and replaced with CYP3A4 and updated figure.
Simvastatin Pathway, Pharmacokinetics pathway diagram (enlarged)