Pravastatin Fibrates

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. 

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). 

Rhabdomyolysis can occur when pravastatin is combined with a fibrate (SEDA-21, 460 11). 

In hepatorenal syndrome (HRS), which is an acute episode, the clearance of renally excreted drugs and metabolites (pravastatin, simvastatin, rosu-vastatin, acipimox, fibrates) may be reduced. During an episode of HRS, anti-hyperlipidaemic medication should be withheld. 

Pravastatin is the statin of choice in this patient as it is least likely to accumulate, is hydrophilic, and is not highly protein bound. The starting dose should be low and should be increased cautiously. Monitoring of LFTs is required. Colestyramine and colestipol may be considered and may help the patient s pruritus. Niacin and acipimox could be used if the pruritus does not worsen. The fibrates should be avoided because of the risk of gallstone formation. Ezetimibe could be considered alone. 

Statins should be avoided. If absolutely necessary, pravastatin could be used, starting at a low dose and with cautious adjustment according to clinical response. The patient s synthetic liver function should be monitored closely. In the event of the slightest deterioration of function, pravastatin should be stopped immediately. Colestyramine/colestipol should be safe to use but may cause a reduction in vitamin K absorption and increase the risk of a bleed. Constipation might induce encephalopathy. The fibrates should be avoided due to their potential effect on coagulopathy. Ezetimibe should be safe to use alone. Acipimox and niacin are gastric irritants and would be best avoided. 

It has been suspected that low concentrations of serum cholesterol might be associated with an increased risk of cancer or overall mortahty. AH fibrates and statins cause cancer in rodents, but the relevance of this finding to man has been questioned (47). In an epidemiological study these risks were almost non-existent after adjusting for confounding factors. However, in the CARE study, breast cancer occurred in one patient in the control group and 12 in the pravastatin group (48). The incidence of cancers. 

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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