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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.
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| Lara M. Mangravite,
Caroline F. Thorn and Ronald M. Krauss |
| March 8, 2006 |
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