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

catalyzes an early, rate-limiting step in cholesterol
biosynthesis. Higher doses of the more potent statins
(e.g., atorvastatin, simvastatin, and rosuvastatin) also
can reduce triglyceride levels caused by elevated VLDL
levels. Some statins also are indicated for raising
HDL-C levels, although the clinical significance of
these effects on HDL-C remains to be proven.
Multiple well-controlled clinical trials have documented the
efficacy and safety of simvastatin, pravastatin, lovastatin, atorvastatin,
and rosuvastatin in reducing fatal and nonfatal CHD events,
strokes, and total mortality (Cholesterol Treatment Trialists’
Collaborators, 2005; Ridker et al., 2008). Rates of adverse events in
statin trials were the same in the placebo groups and in the groups
receiving the drug.
History. Statins were isolated from a mold, Penicillium citrinum,
and identified as inhibitors of cholesterol biosynthesis in 1976 by
MEVASTATIN
FLUVASTATIN
ATORVASTATIN
Endo and colleagues. Subsequent studies by Brown and Goldstein
established that statins act by inhibiting HMG-CoA reductase. The
first statin studied in humans was compactin, renamed mevastatin,
which demonstrated the therapeutic potential of this class of drugs.
Alberts and colleagues at Merck developed the first statin approved
for use in humans, lovastatin (formerly known as mevinolin), which
was isolated from Aspergillus terreus. Six other statins are also available.
Pravastatin and simvastatin are chemically modified derivatives
of lovastatin (Figure 31–2). Atorvastatin, fluvastatin, rosuvastatin,
and pitavastatin are structurally distinct synthetic compounds.
A yeast that grows on rice, monascus purpureus, produces a
series of compounds, one of which, monacolin K, is an inhibitor of
HMG-CoA reductase and is chemically identical to lovastatin. OTC
preparations, known as red yeast rice, contain monacolin K. As with
many nutraceuticals, content of the active principle may vary, and
such preparations should be used with great caution.
Chemistry. The structural formulas of the original statin (mevastatin)
and the seven statins currently available in the U.S. are shown in
LOVASTATIN SIMVASTATIN PRAVASTATIN
HO
O HO O HO O
HO
H 3 C H
O
O
O
O
H
CH
H 3 C H H H 3 C CH H 3 C
3 CH 3 H H H
3 CH 3 CH 3
CO 2 Na
O
O
O
O
O
O
O
OH
F
F
HO
N
CH(CH 3 ) 2
PITAVASTATIN
H 3 C
H 3 C
CO 2 Na
(CH 3 ) 2 CH
OH H O OH OH
N
C
N
COO –
F 2
SO 2 Me
ROSUVASTATIN
Ca 2+ OH OH O Ca 2+
N
Reaction Catalyzed by HMG-CoA Reductase
N
F
N
HO
O –
2
893
CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA
N
OH OH O
O – Ca 2+
CH 3 CH 3 CH
HO HO HO 3
COO – COO – COO –
NADPH + H + NADPH + H +
O OH OH
SCoA
SCoA
HMG-CoA intermediate MEVALONATE
2
Figure 31–2. Chemical structures of the statins and the reaction catalyzed by HMG-CoA reductase.