Lovastatin Fibrates

Reports about the influence of HMG-CoA-reductase inhibitors are conflicting (F7, H42, J8, K22, K29, L15, M3, S33, T5). In general, the effect is minimal or nonexistent some statins, such as simvastatin and lovastatin, are even reported to have an increasing influence (H42, J8, S33, Ul). Fibrates and derivatives are reported to exert a lowering effect (B13, F4, M3). 

Drugs of this series include clofibrate and gemfibrozil, which are derivatives of phenoxy-carboxylic acids—fibrates probucol, which is a substituted fc/y-mercaptophenol and also natural compounds lovastatin, mevastatin, and their analogs. They will be examined separately because it is difficult to explain their action via the entire mechanism. 

Concomitant lipid-lowering therapy - Generally avoid use of lovastatin with fibrates or niacin. If lovastatin is used in combination with gemfibrozil, other fibrates, or lipid-lowering doses (1 g/day or more) of niacin, the dose of lovastatin should not exceed 20 mg/day. 

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. 

Erectile dysfunction has been reported in 12% of 339 men treated with fibrate derivatives or statins, compared with 5.6% of similar patients not taking these drugs (62). The mechanism is unknown and should be confirmed in randomized studies. A class effect has been suggested by the case of a 57-year-old man who had impotence after taking lovastatin for 2 weeks and also when he later tried pravastatin (63). 

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... 

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. 

Millions of people in the world suffer from cardiovascular disease, and it is a leading cause of death in both men and women. Elevation in plasma low-density lipoprotein (LDL) cholesterol levels is a major risk factor for myocardial infarction (heart attack) in these patients. Drugs to reduce dyslipidemia have included niacin and the fibrate class, but each of these has clinical limitations, such as low efficacy or toxic side effects. The development of HMG-CoA reductase inhibitors, or statins, has had an enormous clinical impact on the treatment of heart disease and prevention of heart attack, and these are taken by tens of millions of patients worldwide [1]. One of the first such drugs, lovastatin, was discovered in the 1970s as a fungal natural product [2] and lowered lipid levels in animals and healthy volunteers. Problems with the development of another early statin, compactin, halted advancement of lovastatin to regular clinical use until the late 1980s. Since then. 

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