Statins absorption

Ezetimibe reduces LDL cholesterol by an average of 18% (Table 9-8). However, larger reductions can be seen in some individuals, presumably due to higher absorption of cholesterol. These individuals appear to have a blunted response to statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and modestly increases HDL cholesterol. 

Combination therapy with a statin and ezetimibe is also rational because ezetimibe inhibits cholesterol absorption across the gut border and adds 12% to 20% further reduction when combined with a statin or other drugs. 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

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. ... 

Cholesterol Transport Protein Inhibitor Ezetimibe is the first hypolipidemic agent to act by blocking the absorption of dietary cholesterol at the intestinal level. It represents a novel treatment option for patients with hypercholesterolemia, alone or in combination with statins (Figure 8.60). 

In addition to treatment with the statins, hypercholesterolemia is sometimes treated with the use of nonabsorbable anion-exchange resins like cholestyramine (5.13) and colestipol, which sequester bile acid in the intestine, excrete them, and thus increase their synthesis in the liver by a feedback mechanism. Increased bile acid synthesis increases cholesterol metabolism and also decreases LDL concentrations. Unfortunately, these resins interfere with the absorption of other fats and fat-soluble vitamins (A, D, E, and K). They... 

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. 

In this light, cholesterol absorption has received intense focus for several decades. Although the various statins lower LDL by decreasing endogenous cholesterol synthesis, another approach to prevent excess cholesterol accumulation is to reduce absorption of dietary cholesterol. Doing so also prevents reabsorption of biliary cholesterol, which can have a major impact on overall cholesterol metabolism since recirculation of biliary cholesterol represents a large portion of the cholesterol that transits through the intestine. For recent reviews on mechanisms of cholesterol and lipid absorption, see ref. (1-3). 

The primary goal of therapy is the control of the hypercholesterolemia and prevention of atherosclerotic cardiovascular disease. Patients with heterozygous FH can usually be successfully treated with medications to lower the LDL cholesterol to acceptable levels (Table 14-2). They are generally responsive to treatment with statins, alone or in combination with other drugs, such as bile acid sequestrants (such as cholestyramine) or cholesterol absorption inhibitors (such as ezetimibe) that act additively to upregulate the expression of the functioning LDL receptor as described in the Biochemical Perspectives section. In a few cases, a more aggressive treatment with LDL apheresis (discussed in this section) may have to be considered in order to reach acceptable LDL cholesterol levels. 

The combination of a statin with an inhibitor of cholesterol absorption (e.g., ezetimibe) can lower LDL levels even further. 

Statins are also highly lipophilic if hile salts were required for absorption, this might be reduced. 

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. 

DIGOXIN STATINS High-dose (80 mg) atorvastatin may t digoxin levels Atorvastatin inhibits intestinal P-gp, which t absorption of digoxin Watch for digoxin toxicity... 

STATINS ANION EXCHANGE RESINS Anion-binding resins i the absorption of statins, but the overall lipid-lowering effect is not altered Anion-binding resins bind statins in the intestine Giving the statin 1 hour before or 3-6 hours after the anion exchange resin should minimize this effect... 

The distribution of a compound in the human body can also be partially related to the absorption properties. There are specific transport systems that are expressed in certain tissues that can influence the distribution of the compound. For example, rosuvastatin, a new member of the statin family is transported by the OATP-C carrier system, which is selectively expressed in the liver, making this compound selectively distributed into this organ [27]. In general it is not possible to derive computational models for these selective transport systems since there is not yet enough experimental information and data to support the model building and validation. Nevertheless, there are three properties that are commonly used to describe the distribution of a compound in the human body the solubility, the unspecific binding of the compound to plasma proteins and the volume of distribution. 

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. 

Myalgias related to statin use are quite common, occurring in up to 10 % of patients exposed [19]. Clinicians often measure circulating levels of nonspecific markers of myocyte damage (e.g., CK) to estimate severity. Myalgias accompanied by a mild elevation in serum CK level occur in approximately 1 % of patients exposed [20, 21], Myopathy (CK >10-fold upper limit of normal) is less common, 0.1 %, and rhabdomyolysis (CK >50-fold upper limit of normal) is extremely rare [14, 15]. Graham and colleagues surveyed more than 250,000 statin-exposed patients, and reported rhabdomyolysis rates of 0.000044 events per person-year [18]. Similar rates have been observed for more than 100,000 first-time statin users followed in the UK over a course of 20 months [22], Event rates increase when statins are used in the presence of other medications known to alter their absorption, distribution, metabolism, and elimination (ADME) [23, 24], Event rates also increase with comorbidity (e.g., thyroid disease) [21, 25]. 

The clinical severity of statin-induced muscle toxicity is clearly influenced by variability in enzymes modulating statin disposition (absorption, distribution, metabolism, and elimination, ADME) (Fig. 1) [40], While many statins undergo phase I oxidation (atorvastatin, fluvastatin, lovastatin, simvastatin), the impact of phase I oxidation on others (pitavastatin, pravastatin, rosuvastatin) is very limited [41],... 

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]. 

---