Pathway Pravastatin Pathway, Pharmacokinetics

Pravastatin Pharmacokinetics
Drug-specific representation of the candidate genes involved in transport, metabolism and clearance.
Pravastatin Pathway, Pharmacokinetics
prava prava prava slco2b1 slco1b1 slco2b1 slco1b3 abcb1 abcb11 abcg2 abcc2 slc22a6 slc22a8 abcb1 abcc2 abcg2
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Description

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.
Citation:
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
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History:
Therapeutic Categories:
  • Cardiovascular and hematology agents

Entities in the Pathway

Genes (9)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
pravastatin Active & Inactive metabolites 15199031, 15518608, 15998357, 16103896
pravastatin pravastatin SLCO2B1 12724351, 14610227
pravastatin pravastatin SLC22A6, SLC22A8 12811365, 14729100, 14978359
pravastatin pravastatin SLCO1B1, SLCO1B3, SLCO2B1 12811365, 15116054, 15226675, 15564882, 15864131, 15970799, 16103896, 16198652
pravastatin pravastatin ABCB1, ABCB11, ABCC2, ABCG2 11902809, 15226675, 15616150, 15901796, 15901800, 16107564
pravastatin pravastatin ABCB1, ABCC2, ABCG2 16107564

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