Fenofibrate + statin

The lipid regulator drugs bezafibrate and fenofibrate at initial concentrations of 4.5 and 4.2 ng g-1 in sterile sludge were completely removed after the fungal treatment. The fate of fenofibrate, also present in non-sterile sludge, was the same. Meanwhile, the most abundant atorvastatin, a cholesterol lowering statin, decreased its concentration in 80% and 65% in sterile and non-sterile conditions, respectively. 

Fibrates are being combined with statins to expand their potential in the dyslipidemia market. A recent clinical study examined the effects of rosuvastatin (10) and fenofibrate as mono and combination therapy in hyperlipidemic diabetic patients [43]. In late 2006, large scale Phase III clinical trials of rosuvastatin in combination with a next-generation fibrate, ABT 335, were initiated for evaluation of safety and efficacy in patients with mixed dyslipidemia. 

Fenofibrate appears to be complementary with certain statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin is particularly effective. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

Fibric adds Clofibrate Gemfibrozil Fenofibrate Increase VLtt-catabolism PPAR , agonist LDLi 5-20% HDL t 10%-20% TG i 20%-S0% Gl upset, dyspepsia, gallstones, T LFTs, myopathy Nonmetabolism Warfarin Cyclosporine Statins Liver or severe renal disease primary biliary cirrhosis preexisting gallbladder disease... 

Clinically important, potentially hazardous interactions with cyclosporine, fenofibrate, gemfibrozil, HMG-CoA inhibitors (statins), ritonavir... 

All fibrates increase the lithogenicity of bile. Clofibrate has been associated with increased risk of gallstone formation gemfibrozil and fenofibrate reportedly do not increase biliary tract disease. Renal failure and hepatic dysfunction are relative contraindications to fibrate therapy. Combined statin-fibrate therapy should be avoided in patients with impaired renal function. Gemfibrozil should be used with caution and at a reduced dosage to treat the hyperlipidemia of renal failure. Fibrates should not be used by children or pregnant women. 

It has been an attractive option to use combination therapy of statin and fibrate when HDL remains low but there is no data from RCTs to support this approach. It is ironic that gemfibrozil with the best outcome data should not be used in this context given drug interactions. The results of the FIELD trial with fenofibrate as sole therapy were disappointing [59] however, a combination trial with fenofibrate and statin in type 2 diabetes, the ACCORD study, is in progress. 

Fenofibrate (propan-2-yl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate), a fibric acid derivative (Fig. 7.6), mainly exerts its effect via the activation of speciflc nuclear receptor called peroxisome proliferator-activated receptor alpha (PPARa). This PPARa agonist is primarily used to decrease the cholesterol levels in cardiovascular diseases patients. Like statins, fenofibrate also reduces triglycerides and low- and very low density protein levels. It also increases high-density lipoprotein levels in the body. Fenofibrate also has nonlipid (i.e., pleiotropic) effects (reduction in fibrinogen, C-reactive protein, and uric acid levels and improvement in the flow-mediated dilatation). 

Interest in fenofibrate has re-emerged with the near demise of gemfibrozil in some countries, once it became apparent that a statin+fenofibrate combination was highly likely to be safe. It is currently by far the preferred fibrate for the management of hypertriglyceridemia or in combination with a statin for treating combined hyperlipidemia. Different studies with a variety of statins have uniformly found no greater incidence of serious adverse reactions when fenofibrate is added compared with placebo. 

The authors of a major review of rosuvastatin concluded that its adverse reaction profile resembles that of other commonly used statins [34 ]. Increments in fiver enzymes are in most cases minor and of minimal concern, renal dysfunction is quite uncommon, myopathy is unusual, and rhab-domyolysis is rare. Interactions with other drugs are fisted but no new information given. Combinations with fenofibrate, omega-3 fatty acids, ezetimibe, rifampicin, and clopidogrel appear to be safe. 

LC-ESI-MS/MS has been used to determine lipid-regulating agents, including the fibrates and statins classes in water. For the fibrates, N1 mode was generally employed with deprotonated molecules [M — H] at m/z 213 for clofibric acid, m/z 249 for gemfibrozil, and m/z 360 for bezafibrate [85,87,140,147]. However, PI mode was also used for fenofibrate and bezafibrate [86]. In ESI(—) tandem MS mode, the deprotonated molecule of clofibric... 

---