Fibrates absorption

Fibrate absorption may be reduced in the presence of cholestasis. Metabolism will be reduced in liver dysfunction. Renal failure increases the risk of myopathy with fibrate use. During an episode of HRS, anti-hyperlipidaemic medication should be withheld. 

Another therapeutic class to be briefly discussed is that of the lipid-lowering agents known as fibrates, e.g., clofibrate and fenofibrate (8.5). Here also, the acidic metabolite is the active form clofibrate (an ethyl ester) is rapidly hydrolyzed to clofibric acid by liver carboxylesterases and blood esterases [11], Human metabolic studies of fenofibrate (8.5), the isopropyl ester of fenofibric acid, showed incomplete absorption after oral administration, while hydrolysis of the absorbed fraction was quantitative [12], This was followed by other reactions of biotransformation, mainly glucuronidation of the carboxylic acid group. 

As discussed above, obesity is associated with dyslipidemia, a condition where high levels of low-density lipoprotein cholesterol (LDL-C) is common. Elevated LDL-C is strongly associated with an elevated risk of coronary artery disease and for this reason a number of lipid-lowering therapies that target LDL-C have been developed. These include bile-acid sequestrants (BAS), statins (HMG-CoA reductase inhibitors), cholesterol absorption inhibitors, and fibrates. ... 

A recently developed antihyperlipidemic is ezetimibe (Zetia, A.113) (Figure A.31). Ezetimibe inhibits the absorption of cholesterol across the intestinal wall. Like fibrates, ezetimibe is often prescribed with statins, although the effectiveness of ezetimibe has recently been called into question. A compound that may soon be approved for the treatment of high cholesterol is anacetrapib (A.114). Anacetrapib, a product of Merck, is currently in phase III trials. The compound inhibits cholesteryl ester transfer protein (CETP). The net effect of CETP inhibition is elevated HDL cholesterol and lower LDL cholesterol levels. 

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

The fibrates are very lipophilic but it is not clear whether they require bile salts for absorption. They are also highly protein bound. Hyperbili-rubinaemia may cause displacement from plasma proteins, leading to increased free drug concentrations. 

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. 

Lipid-lowering drugs. Fibrates, and some statins, enhance anticoagulant effect. Colestyramine is best avoided for it may impair the absorption of both warfarin and vitamin K. 

Currently available treatments against atherosclerosis include cholesterol-lowering drugs such as statins, fibrates, nicotinic acid (NA) [8-13] and the cholesterol intestinal absorption inhibitor, ezetimibe (Fig. 1) [14]. 

Statins Ezitimibe Omega-3 triglycerides Bile acid sequestrants Fibrates Nicotinic acid derivatives Inhibit HMG-CoA reductase Inhibits absorption of cholesterol from the intestine Inhibit VLDL synthesis in the liver Bind bile acids in the intestine Lower levels of circulating VLDLs and LDLs by unknown mechanism Reduce the release of VLDLs from the liver... 

Drugs Drug therapy can reduce fat absorption from the intestine (resins), modify hepatic cholesterol synthesis (HMG-CoA reductase inhibitors), decrease secretion of lipoproteins (niacin), increase peripheral clearance of lipoproteins (fibrates). and can perhaps exert other effects. These drugs are all given orally (Figure 35-1). 

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. 

Fibrates have excellent bloavallablllty and are extensively bound to plasma proteins. Because food can significantly enhance their oral absorption, these compounds should be taken either with or just before meals. Fenofibrate was available in Europe and elsewhere as standard tablet and capsule formulations for many years before its approval and marketing in the United States, where it was ihtroduced only after the development of a micronized formulation that allowed better oral absorption, a lower daily dose, and once-daily administration. A 67-mg dose of micronized fenofibrate is bioequivalent to a 100-mg dose of nonmicronized drug. Since that time, two additional tablet formulations have been developed. Abbott Laboratories currently markets TriCor as 48- and 145-mg tablets. The 48-mg formulation is equivalent to previous 54- and 67-mg formulations, and the 145-mg tablet is equivalent to previous 160- and 200-mg formulations. As noted in Table 30.10, fenofibrate is currently available in all of these strengths. 

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