Fibrates Atorvastatin

Concomitant lipid-lowering f/ erapy-Atorvastatin may be used in combination with a bile-acid-binding resin for additive effect. Generally, avoid the combination of HMG-CoA reductase inhibitors and fibrates. 

Secondary uric acid-lowering drugs such as feno-fibrate, atorvastatin and losartan all are mild-to-moderate uricosurics. 

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. 

The incidence of rhabdomyolysis in patients taking different statins and fibrates, alone and in combination, has been estimated using data from 11 managed health care plans across the USA (43). The incidences of rhabdomyolysis were 0.44 per 10 000 person-years of treatment with atorvastatin, pravastatin, or simvastatin, 5.34 with cerivastatin, and 2.82 with fibrates. The incidence increased to 5.98 when atorvastatin, pravastatin, or simvastatin was with a fibrate, and to 1035 when cerivastatin was combined with a fibrate. 

The absorption of highly lipophilic drugs (atorvastatin, simvastatin, ezetimibe, fibrates) may be reduced in cholestasis if they require bile salts for their absorption. 

FIBRATES STATINS Gemfibrozil may t atorvastatin, rosuvastatin and simvastatin levels (risk of myopathy with simvastatin) Uncertain Avoid co-administration of simvastatin and gemfibrozil. When using other statins, warn patients to watch for the features of myopathy... 

In patients taking fenofibrate and atorvastatin, increased concentrations of plasma homocysteine were attributed to an action of the fibrates themselves and not indirectly via their lipid-lowering effect (8). Concomitant administration of folic acid, at least in part, offset this adverse effect... 

F Before initiating statin therapy, it is recommended to have baseline measurements of the lipoprotein profile and LFTs. If the LFTs are more than three times the upper limit of normal (ULN), statins should be avoided. If the LFTs are less than three times the ULN, statin therapy can be initiated, but the patient should be monitored closely. If LFTs become elevated, reversal of the transaminase elevation is common upon discontinuation of the statin. Some experts also recommend obtaining a baseline creatine kinase (CK) level. If the CK level is more than 10 times the ULN while on a statin, the statin should be discontinued. The combination of a statin with niacin or a fibrate should be used cautiously because of an increased risk of myopathy. Although most statins are taken at dinner or bedtime, atorvastatin can be taken at any time of the day due to its longer T /i ( 14 hours). Lovastatin should be taken with food because this increases its bioavailabilty. 

Loops ethacrynic acid, furosemide, torsemide Bipyridines inamrinone, amrinone, milrmone, P agonists dobutamine, dopamine Statins lovastatin atorvastatin, etc Fibrates gemfibrozil... 

In addition to these newer agents, there are currently three fibrate-based combinations with HMG-CoA reductase inhibitors in clinical trials. In phase III, Sciele has fenofibrate/pravastatin combination and AstraZeneca and Abbott have rosuvastatin/choline fenofibrate (ABT335), while in phase II, Life Cycle Pharma have atorvastatin / fenofibrate. 

Certain drug combinations present challenges. Because resins interfere with the absorption of certain reductase inhibitors (pravastatin, cerivastatin, atorvastatin, and fluvastatin), these must be given at least 1 hour before or 4 hours after the resins. The combination of reductase inhibitors with either fibrates or niacin may increase the risk of myopathy. 

The plasma levels of lovastatin, simvastatin, atorvastatin and pravastatin are increased by gemfibrozil, the levels of fluvastatin are increased by bezaflbrate, and the levels of pravastatin are increased by fenoflbrate. No pharmacokinetic interactions occur with the combinations of fluvastatin with gemfibrozil, lovastatin with bezaflbrate, and pravastatin, rosuvastatin or simvastatin with fenoflbrate. Both statins and fibrates are known to cause rhabdomyolysis, and their concurrent use increases the risk of this reaction. 

In a review of the FDA spontaneous reports of statin-associated rhabdomyolysis covering the period November 1997 to March 2000, fibrates (unspeeified) were potentially implieated in 10 of 73 cases of rhabdomyolysis seen with atorvastatin, 4 of 10 with fluvastatin, 5 of 40 with lovastatin, 6 of 71 with pravastatin, and 33 of 215 with simvastatin. 

Prueksaritanont, T. Tang, C. (Jiu, Y. Mu, L. Subramanian, R. Lin, J.H. Effects of fibrates on metabolism of statins in human hepatocytes, Drug Metab.Dispos., 2002, 30, 1280-1287. [cerivastatin simvastatin atorvastatin rosuvastatin pravastatin]... 

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