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

896 Due to extensive first-pass hepatic uptake, systemic bioavailability
of the statins and their hepatic metabolites varies between 5%
and 30% of administered doses. The metabolites of all statins, except
fluvastatin and pravastatin, have some HMG-CoA reductase
inhibitory activity (Bellosta et al., 2004). Under steady-state conditions,
small amounts of the parent drug and its metabolites produced
in the liver can be found in the systemic circulation. After the lactones
of simvastatin and lovastatin are transformed in the liver to SVA
and LVA, small amounts of these active inhibitors of HMG-CoA
reductase, as well as small amounts of the lactone forms, can be found
in the systemic circulation. In the plasma, >95% of statins and their
metabolites are protein bound, with the exception of pravastatin and
its metabolites, which are only 50% bound (Schachter, 2005).
After an oral dose, plasma concentrations of statins peak in
1-4 hours. The t 1/2
of the parent compounds are 1-4 hours, except
in the case of atorvastatin and rosuvastatin, which have half-lives of
~20 hours, and simvastatin with a t 1/2
~12 hours (Ieiri et al., 2007).
The longer t 1/2
of atorvastatin and rosuvastatin may contribute to
their greater cholesterol-lowering efficacy (Corsini et al., 1999). The
liver biotransforms all statins, and more than 70% of statin metabolites
are excreted by the liver, with subsequent elimination in the
feces (Bellosta et al., 2004). Inhibition by other drugs of OATP1B1,
which transports several statins into hepatocytes, and inhibition or
induction of CYP3A4 by a variety of pharmacological agents provide
rationales for drug-drug interactions involving statins (Shitara
and Sugiyama, 2006).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Adverse Effects and Drug Interactions
Hepatotoxicity. Initial post-marketing surveillance studies of the
statins revealed an elevation in hepatic transaminase to values greater
than three times the upper limit of normal, with an incidence as great
as 1%. The incidence appeared to be dose related. However, in the
placebo-controlled outcome trials in which 10- to 40-mg doses of
simvastatin, lovastatin, fluvastatin, atorvastatin, pravastatin, or rosuvastatin
were used, the incidence of 3-fold elevations in hepatic
transaminases was 1-3% in the active drug treatment groups and
1.1% in placebo patients (Law et al., 2006; Ridker et al., 2008). No
cases of liver failure occurred in these trials. Although serious hepatotoxicity
is rare, 30 cases of liver failure associated with statin use
were reported to the FDA between 1987 and 2000, a rate of about
one case per million person-years of use (Law et al., 2006). It is
therefore reasonable to measure alanine aminotransferase (ALT) at
baseline and thereafter when clinically indicated.
Observational studies and a prospective trial suggest that
transaminase elevations in patients with nonalcoholic fatty liver disease
and hepatitis C are not at risk of statin-induced liver toxicity
(Alqahtani and Sanchez, 2008; Chalasani et al., 2004; Lewis et al.,
2007; Norris et al., 2008). This is important, as many insulin-resistant
patients are affected by nonalcoholic fatty liver disease and have elevated
transaminases. As insulin resistance is associated with
increased CVD risk, insulin-resistant patients, especially those
with type 2 diabetes mellitus, benefit from lipid-lowering therapy
with statins (Cholesterol Treatment Trialists’ Collaborators, 2008). It
is reassuring that these patients with elevated transaminases can
safely take statins.
Myopathy. The major adverse effect associated with statin use is
myopathy (Wilke et al., 2007). Between 1987 and 2001, the FDA
recorded 42 deaths from rhabdomyolysis induced by statins (excluding
cerivastatin, which has been withdrawn from the market worldwide).
This is a rate of one death per million prescriptions (30-day
supply). In the statin trials described earlier (under “Hepatotoxicity”),
rhabdomyolysis occurred in eight active drug recipients versus five
placebo subjects. Among active drug recipients, 0.17% had CK values
exceeding 10 times the upper limit of normal; among placebo-treated
subjects, the incidence was 0.13%. Only 13 out of 55 drug-treated subjects
and 4 out of 43 placebo subjects with greater than 10-fold elevations
of CK reported any muscle symptoms (Law et al., 2006).
The risk of myopathy and rhabdomyolysis increases in proportion
to statin dose and plasma concentrations. Consequently, factors
inhibiting statin catabolism are associated with increased
myopathy risk, including advanced age (especially >80 years of age),
hepatic or renal dysfunction, perioperative periods, multi-system disease
(especially in association with diabetes mellitus), small body
size, and untreated hypothyroidism (Pasternak et al., 2002;
Thompson et al., 2003). Concomitant use of drugs that diminish
statin catabolism or interfere with hepatic uptake is associated with
myopathy and rhabdomyolysis in 50-60% of all cases (Law and
Rudnicka, 2006; Thompson et al., 2003). Thus, avoiding these drug
interactions should reduce myopathy and rhabdomyolysis by about
one-half (Law and Rudnicka, 2006). The most common statin interactions
occurred with fibrates, especially gemfibrozil (38%),
cyclosporine (4%), digoxin (5%), warfarin (4%), macrolide antibiotics
(3%), mibefradil (2%), and azole antifungals (1%) (Thompson
et al., 2003). Other drugs that increase the risk of statin-induced
myopathy include niacin (rare), HIV protease inhibitors, amiodarone,
and nefazodone (Pasternak et al., 2002).
There are a variety of pharmacokinetic mechanisms by which
these drugs increase myopathy risk when administered concomitantly
with statins. Gemfibrozil, the drug most commonly associated
with statin-induced myopathy, inhibits both uptake of the active
hydroxy acid forms of statins into hepatocytes by OATP1B1 and
interferes with the transformation of most statins by glucuronidases
(Prueksaritanont et al., 2002a; Prueksaritanont et al., 2002b;
Prueksaritanont et al., 2002c). Primarily due to inhibition of
OATP1B1-mediated hepatic uptake, co-administration of gemfibrozil
nearly doubles the plasma concentration of the statin hydroxy
acids (Neuvonen et al., 2006). Other fibrates, especially fenofibrate,
do not interfere with the glucuronidation of statins and pose less risk
of myopathy when used in combination with statin therapy. (For
reviews of statin interactions with other drugs, see Bellosta et al.,
2004 and Neuvonen et al., 2006). Concomitant therapy with simvastatin,
80 mg daily, and fenofibrate, 160 mg daily, results in no
clinically significant pharmacokinetic interaction (Bergman et al.,
2004). Similar results were obtained in a study of low-dose rosuvastatin,
10 mg daily, plus fenofibrate, 67 mg three times a day. When
statins are administered with niacin, the myopathy probably is
caused by an enhanced inhibition of skeletal muscle cholesterol synthesis
(a pharmacodynamic interaction).
Drugs that interfere with statin oxidation are those metabolized
primarily by CYP3A4 and include certain macrolide antibiotics
(e.g., erythromycin); azole antifungals (e.g., itraconazole);
cyclosporine; nefazodone, a phenylpiperazine antidepressant; HIV
protease inhibitors; and amiodarone (Alsheikh-Ali and Karas, 2005;
Bellosta et al., 2004; Corsini, 2003). These pharmacokinetic interactions
are associated with increased plasma concentrations of statins