Pathway Atorvastatin/Lovastatin/Simvastatin Pathway, Pharmacokinetics

Drug-specific representation of the candidate genes involved in transport, metabolism and clearance.
Atorvastatin/Lovastatin/Simvastatin Pathway, Pharmacokinetics
atorva lova simva atorva lova simva atorva lova simva cyp3a5 cyp3a4 slco1b1 slco2b1 slco1b3 cyp3a4 cyp3a5 cyp2c9 cyp2c19 cyp2c8 cyp2d6 ugt1a1 ugt1a3 ugt2b7 abcb1 abcc2
clickable pathway icons
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Statins inhibit endogenous cholesterol production by competitive inhibition of HMG-CoA reductase (HMGCR), the enzyme that catalyzes conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol synthesis. This pathway delineates genes involved in statin pharmacogenomics, including genes involved in mediating the pharmacodynamic (PD) effects of statins on plasma lipoprotein metabolism and those involved in the pharmacokinetics (PK) effects of the drug transport and metabolism.

The statin PD view depicts the effects of inhibition of HMG CoA reductase on major aspects of hepatic cholesterol metabolism, and selected gene products that can modulate the effects of statins on metabolism and transport of plasma lipoproteins that affect atherosclerosis and cardiovascular disease risk.

The statin PK view depicts a generalized view of the pharmacokinetics of this drug class, representing the superset of all genes with a reported influence on statin transport and metabolism. Statins are dosed orally and enter the systemic circulation through intestinal cells both passively and by active transport via the ABC and SLC gene family transporters. The major organs of metabolism and elimination include the liver and, to a lesser extent, the kidney. Metabolism is catalyzed by CYP and UGT gene family enzymes. The main pathway of elimination is ABC transporter mediated biliary excretion.

The pharmacokinetics of individual statin drugs are influenced by their hydrophobicity. The more hydrophilic compounds, pravastatin in particular, require active transport into the liver, are less metabolized by the cytochrome P450 (CYP) family, and exhibit more pronounced active renal excretion, while the less hydrophilic compounds are transported by passive diffusion and are better substrates for both CYP enzymes and transporters involved in biliary excretion. Although simvastatin and lovastatin are both given as lactone prodrugs and converted to the active beta-hydroxy form, the mechanism for this does not appear to be via CYP pathways and is not depicted here. Additional drug-specific views can be selected that display the pharmacokinetic pathways for atorvastatin, lovastatin and simvastatin, fluvastatin, pravastatin and rosuvastatin.

Clicking on the genes will redirect you to information about the gene and its variants, clicking on drugs will take you to the drug information. Externally linked signaling pathways address some of the biologically important effects of statins in the liver and other tissues that result from altered metabolism of intermediates in the cholesterol synthetic pathway.

Authors: Lara M. Mangravite, Caroline F. Thorn, Ronald M. Krauss.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Therapeutic Categories:
  • Cardiovascular and hematology agents

Entities in the Pathway

Genes (14)

Drugs/Drug Classes (3)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
atorvastatin Active & Inactive metabolites CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT1A3, UGT2B7 12848784, 15801541, 16388406
atorvastatin Active & Inactive metabolites CYP3A4, CYP3A5
lovastatin Active & Inactive metabolites CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT1A3, UGT2B7 12848784, 15801541, 16388406
lovastatin Active & Inactive metabolites CYP3A4, CYP3A5
simvastatin Active & Inactive metabolites CYP3A4, CYP3A5
simvastatin Active & Inactive metabolites CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT1A3, UGT2B7 12848784, 15801541, 16388406
atorvastatin atorvastatin SLCO1B1, SLCO1B3, SLCO2B1
atorvastatin atorvastatin ABCB1, ABCC2
lovastatin lovastatin SLCO1B1, SLCO1B3, SLCO2B1
lovastatin lovastatin ABCB1, ABCC2
simvastatin simvastatin SLCO1B1, SLCO1B3, SLCO2B1
simvastatin simvastatin ABCB1, ABCC2

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Related Publications

Effect of polymorphisms in CYP3A4, PPARA, NR1I2, NFKB1, ABCG2 and SLCO1B1 on the pharmacokinetics of lovastatin in healthy Chinese volunteers. Pharmacogenomics. 2017. Zhao Guilian, Liu Mei, Wu Xiujun, Li Guofei, Qiu Feng, Gu Jingkai, Zhao Limei. PubMed
The Clinical Pharmacogenomics Implementation Consortium: CPIC Guideline for SLCO1B1 and Simvastatin-Induced Myopathy. Clinical pharmacology and therapeutics. 2012. Wilke R A, Ramsey L B, Johnson S G, Maxwell W D, McLeod H L, Voora D, Krauss R M, Roden D M, Feng Q, Cooper-Dehoff R M, Gong L, Klein T E, Wadelius M, Niemi M. PubMed