Does differing metabolism by cytochrome P450 have clinical importance?

Abstract

The cytochrome P450 (CYP) is a group of enzymes that oxidatively modify drugs to a more water-soluble form for renal excretion. Nearly 50% of all clinically used medications and endogenous steroids are metabolized by the CYP enzyme 3A4, which explains why many of the important potential drug interactions involved this enzyme. Despite an excellent safety record, CYP 3A4 statins (lovastatin, simvastatin, atorvastatin) taken concomitantly with a potent CYP 3A4 inhibitor may increase the risk for adverse events (myopathy, rhabdomyolysis). This article describes the clinical significance of CYP metabolism as the pathways relate to the use of statins, including brief discussions on statins, fibrates, cyclosporine, and calcium channel blockers. In light of these potential interactions, continued vigilance by physicians is necessary to ensure the safe use of statins.

Farnesyl and Geranylgeranyl Transferase Inhibitors Induce G1 Arrest by Targeting the Proteasome

“…They are administered in a prodrug, lactone (inactive) form, and are subsequently metabolized into the hydroxy acid (active) form by the cytochrome P450 liver enzymes (40,41). Previously, we have shown that whereas the hydroxy acid form of statins directly inhibits HMGR in the cholesterol pathway, the lactone form functions through modulation of the proteasome (14).…”

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

“…19 -21 Some of the drug to drug interactions involve specific interactions with the cytochrome P-450 drug-metabolizing system, especially those involving the 3A4 isozyme. 22,23 The combination of statins with a fibrate is attractive for persons who have both high serum cholesterol and high triglycerides or for those who continue to have elevated triglycerides after reaching their LDL-cholesterol target on statin therapy. However, there may be a concern about an increased danger of developing myopathy with this combination.…”

“…Some have proposed that statin interaction with the cytochrome P-450 hepatic enzyme system might be related to myopathy. 22 Support for this concept comes, in part, from the known enhanced toxicity when statins are administered with agents sharing metabolism by the same cytochrome isoforms. Finally, it has been shown that exercise in combination with lovastatin produces greater creatine kinase elevations than those produced by exercise alone, suggesting that statins can exacerbate exercise-induced skeletal muscle injury.…”

Combination lipid-lowering therapy in diabetes

“…Rhabdomyolysis, which is myopathy with associated renal damage, is estimated to occur in approximately one in 10,000 patients treated with simvastatin [16•]. In clinical practice, which includes patients at high risk for myopathy, such as the elderly, women, individuals with a smaller body mass index, renal impairment, or on a potential interacting drug, the incidence of myopathy may be significantly higher [17]. The myopathy rate for patients on 80 mg of simvastatin in conjunction with amiodarone was documented in 6% of patients, and for patients receiving both verapamil and simvastatin, the myopathy rate was 0.63% compared with 0.061% for patients taking simvastatin without a calcium channel blocker [15].…”

“…Myopathy is dose dependent [22,23] and occurs more frequently with statins (eg, lovastatin, simvastatin, and atorvastatin) in conjunction with drugs that inhibit the cytochrome P450 3A4 pathway and in patients who have impaired drug metabolism, such as the elderly or those with renal insufficiency [17]. Therefore, pharmacokinetic trials of statins in combination with other lipid-altering drugs are very useful in predicting potentially clinically insignificant drug interactions.…”