Figure 1. Mechanism of Action of Statins and Potential Interactions with Estrogen.

Orally administered statins (open circles) enter intestinal cells passively or through active transport. Simvastatin, atorvastatin, and lovastatin may undergo oxidative metabolism by CYP3A4/5 enzymes (triangles) within the intestinal cell. Next, statins are transported through the bloodstream into hepatocytes. OATP1B1 is one of several transporters responsible for hepatic uptake of statins. In the liver, statins competitively bind to the active site of HMG-CoA reductase, inhibiting the conversion of HMG-CoA to mevalonic acid (depicted by blunt-ended arrow), which is an early step in the cholesterol synthesis pathway (shown in center of hepatocyte). Simvastatin, lovastatin, and atorvastatin are metabolized by CYP3A4/5, while fluvastatin is metabolized primarily by CYP2C9 (metabolites depicted by triangles). Pravastatin, pitavastatin, and rosuvastatin undergo limited cytochrome P450-mediated metabolism. In addition, statins may also undergo glucuronidation or sulfation mediated by polymorphic glucuronosyltransferase and sulfotransferase enzymes (metabolites shown as squares). Finally, statins may be transported out of the hepatocyte and into bile for elimination or into the bloodstream for renal elimination.

Estrogens (filled circles) may be administered orally or transdermally, or may be endogenously produced. Orally administered estrogens must pass through the intestinal cells where CYP3A4/5-mediated metabolism may occur (metabolites shown as inverted triangles). Transdermally administered estrogens and endogenous estrogens enter the hepatocytes from the blood where they may be metabolized by CYP3A4/5 and/or undergo sulfate and glucuronide conjugation (diamonds), similar to statins. Sulfate- and glucuronide-conjugated estrogens may use the same transporters as statins, including OATP1B1.