DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

been reported to potentiate the action of oral anticoagulants, in part
by displacing them from their binding sites on albumin. Careful
monitoring of the prothrombin time and reduction in dosage of the
anticoagulant may be appropriate when treatment with a fibrate is
begun.
A myopathy syndrome occasionally occurs in subjects taking
clofibrate, gemfibrozil, or fenofibrate and may occur in up to 5% of
patients treated with a combination of gemfibrozil and higher doses
of statins. To diminish the risk of myopathy, statin doses should be
reduced when combination therapy of a statin plus a fibrate is
employed. Several drug interactions may contribute to this adverse
response. Gemfibrozil inhibits hepatic uptake of statins by OATP1B1.
Gemfibrozil also competes for the same glucuronosyl transferases
that metabolize most statins. As a consequence, levels of both drugs
may be increased when they are co-administered (Prueksaritanont
et al., 2002b; Prueksaritanont et al., 2002c). Patients taking this combination
should be instructed to be aware of the potential symptoms
and should be followed at 3-month intervals with careful history and
determination of CK values until a stable pattern is established.
Patients taking fibrates with rosuvastatin should be followed especially
closely even if low doses (5-10 mg) of rosuvastatin are
employed until there is more experience with and knowledge of the
safety of this specific combination. Fenofibrate is glucuronidated by
enzymes that are not involved in statin glucuronidation. Thus, fenofibrate-statin
combinations are less likely to cause myopathy than combination
therapy with gemfibrozil and statins.
All of the fibrates increase the lithogenicity of bile. Clofibrate
use has been associated with increased risk of gallstone formation.
Renal failure is a relative contraindication to the use of fibric
acid agents, as is hepatic dysfunction. Combined statin-fibrate therapy
should be avoided in patients with compromised 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.
Therapeutic Use. Clofibrate is available for oral administration. The
usual dose is 2 g/day in divided doses. This compound is little used
but may be useful in patients who do not tolerate gemfibrozil or
fenofibrate. Gemfibrozil (LOPID) usually is administered as a 600-mg
dose taken twice a day, 30 minutes before the morning and
evening meals. Fenofibrate is available in two different formulations.
The first preparation developed is the dimethylethyl ester of
fenofibric acid, which is poorly water soluble and poorly absorbed.
After uptake by the liver, this compound is hydrolyzed to produce
fenofibric acid, which is the active moiety. Recently, a choline salt
of fenofibric acid that is highly soluble in water and readily
absorbed was developed. The effects of both formulations, however,
are similar with respect to changes in plasma lipid concentrations
(Grundy et al., 2005; Jones et al., 2009). The dimethylethyl
ester preparations of fenofibric acid include TRICOR and LOFIBRA.
The tricor brand of fenofibrate is available in tablets of 48 and 145
mg. The usual daily dose is 145 mg. Generic fenofibrate (LOFIBRA)
is available in capsules containing 67, 134, and 200 mg. TRICOR,
145 mg, and LOFIBRA, 200 mg, are equivalent doses. The choline
salt of fenofibric acid (TRILIPIX) is available in capsules of 135 and
45 mg. TRILIPIX, 135 mg, is equivalent to TRICOR, 145 mg, and LOFI-
BRA, 200 mg. Choline fenofibrate is indicated for combination therapy
with statins (Jones et al., 2009). Fibrates are the drugs of choice for
treating hyperlipidemic subjects with type III hyperlipoproteinemia
as well as subjects with severe hypertriglyceridemia (triglycerides
>1000 mg/dL) who are at risk for pancreatitis. Fibrates appear to
have an important role in subjects with high triglycerides and low
HDL-C levels associated with the metabolic syndrome or type 2
diabetes mellitus (Robins, 2001). When fibrates are used in such
patients, the LDL levels need to be monitored; if LDL levels rise,
the addition of a low dose of a statin may be needed. Many experts
now treat such patients first with a statin (Heart Protection Study
Collaborative Group, 2003) and then add a fibrate, based on the
reported benefit of gemfibrozil therapy. However, statin-fibrate
combination therapy has not been evaluated in outcome studies
(American Diabetes Association, 2004). If this combination is used,
there should be careful monitoring for myopathy.
Ezetimibe and the Inhibition of Dietary
Cholesterol Uptake
Ezetimibe is the first compound approved for lowering
total and LDL-C levels that inhibits cholesterol absorption
by enterocytes in the small intestine. It lowers LDL-
C levels by ~20% and is used primarily as adjunctive
therapy with statins.
EZETIMIBE
History. Ezetimibe (SCH58235) was developed by pharmaceutical
chemists studying inhibition of intestinal ACAT. Several compounds
were found to inhibit cholesterol absorption, but by inhibiting intestinal
cholesterol transport rather than ACAT.
Mechanism of Action. Ezetimibe inhibits luminal cholesterol
uptake by jejunal enterocytes, by inhibiting the
transport protein NPC1L1 (Altmann et al., 2004; Davis
et al., 2004).
In wild-type mice, ezetimibe inhibits cholesterol absorption
by about 70%; in NPC1L1 knockout mice, cholesterol absorption is
86% lower than in wild-type mice, and ezetimibe has no effect on
cholesterol absorption (Altmann et al., 2004). Ezetimibe does not
affect intestinal triglyceride absorption. In human subjects, ezetimibe
reduced cholesterol absorption by 54%, precipitating a compensatory
increase in cholesterol synthesis that can be inhibited with a
cholesterol synthesis inhibitor such as a statin (Sudhop et al., 2002).
There also is a substantial reduction of plasma levels of plant sterols
(campesterol and sitosterol concentrations are reduced by 48% and
41%, respectively), indicating that ezetimibe also inhibits intestinal
absorption of plant sterols.
The consequence of inhibiting intestinal cholesterol absorption
is a reduction in the incorporation of cholesterol into chylomicrons.
The reduced cholesterol content of chylomicrons diminishes
the delivery of cholesterol to the liver by chylomicron remnants. The
903
CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA