What is the metabolic pathway of a statin (HMG-CoA reductase inhibitor)?

From the Guidelines

Statin metabolism primarily occurs through the cytochrome P450 enzyme system, with the CYP3A4 and CYP2C9 enzyme systems being the most prevalent subcategories for statin metabolism. The specific metabolic pathway varies by statin type, with simvastatin and lovastatin undergoing significant CYP3A4 metabolism, and atorvastatin undergoing a lesser amount as one of its minor metabolic pathways 1. In contrast, fluvastatin, pitavastatin, and rosuvastatin require CYP2C9 for their metabolism. Additionally, glucuronidation is another metabolic pathway for statins, resulting in statin conversion to glucuronide conjugates, which can be inhibited by certain nonstatin medications, such as gemfibrozil 1.

Key points to consider in statin metabolism include:

• The extent of renal excretion, which varies among statins, with atorvastatin having the least amount of renal excretion (<2%) 1
• The potential for drug-drug interactions, particularly with medications that inhibit CYP3A4 or CYP2C9, which can increase systemic drug exposure and lead to adverse effects 1
• The importance of considering liver function and impaired glomerular filtration rate when selecting a statin, as certain statins may be more susceptible to decreased drug excretion in these patients 1

Understanding the metabolic pathways of different statins is crucial for predicting drug interactions and selecting the most appropriate statin for patients with specific clinical characteristics, such as liver impairment or concomitant use of other medications that use the same metabolic pathways.

From the FDA Drug Label

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme

• Metabolism of atorvastatin: Atorvastatin is metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products.
• Active metabolites: Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
• Enzyme involved: Atorvastatin metabolism is mediated by cytochrome P450 3A4.
• Key point: The metabolism of atorvastatin is complex and involves the formation of active metabolites that contribute to its pharmacological effects 2.

The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxy isomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxy isomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0. 66).

• Metabolism of pravastatin: Pravastatin is metabolized through isomerization and enzymatic ring hydroxylation.
• Major metabolites: The major metabolites of pravastatin are 6-epi pravastatin, 3α-hydroxy isomer of pravastatin (SQ 31,906), and SQ 31,945.
• Hepatic extraction: Pravastatin undergoes extensive first-pass extraction in the liver.
• Key point: The metabolism of pravastatin involves the formation of metabolites with reduced HMG-CoA reductase inhibitory activity 3.

From the Research

Statin Metabolism

• Statins are metabolized by the cytochrome P450 family of enzymes, with CYP3A4 and CYP2C9 being the main statin-metabolizing enzymes 4
• The metabolism of statins occurs primarily in the liver, with human liver microsomes (HLMs) showing extensive metabolism of statin lactones, such as atorvastatin lactone and simvastatin lactone 4
• In human intestine microsomes (HIMs), only atorvastatin lactone and simvastatin lactone exhibited notable metabolism, with intrinsic clearance values corresponding to 20% of those observed in HLMs 4

Enzyme-Specific Metabolism

• CYP3A4 and CYP2C9 are involved in the metabolism of various statins, with CYP3A4 being the primary enzyme responsible for the metabolism of atorvastatin, simvastatin, and lovastatin 5, 4
• CYP2C9 is also involved in the metabolism of fluvastatin, with an IC50 value of 4 microM 5
• Pravastatin is not significantly metabolized by CYP3A4 or CYP2C9, and its metabolism is primarily mediated by other enzymes 5

Transporter-Mediated Metabolism

• Statins are also subject to transporter-mediated metabolism, with uptake transporters such as SLCO1B1 and SLCO2B1, and efflux transporters such as ABCB1 and ABCG2, playing a role in their disposition 6
• Atorvastatin treatment has been shown to increase the expression of SLCO2B1, ABCB1, and ABCG2 in human liver tissue, potentially affecting the efficacy and safety of statin treatment 6