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PHARMACOTHERAPY Volume 21, Number 6, 2001
Simvastatin (on formulary at our institution)
simvastatin and pravastatin potently inhibit
cholesterol synthesis in liver cells. Pravastatin is
unique in that it is the only statin that undergoes
selective uptake into hepatocytes. Due to its low
lipid solubility, a carrier-mediated transport
process specific to hepatocytes is necessary for
cellular uptake.8 Simvastatin has passed the
blood-brain barrier in in vitro studies, whereas
pravastatin does not distribute into cerebrospinal
fluid. Both drugs undergo significant biliary
excretion, with 60% of simvastatin and 71% of
pravastatin appearing in the feces after oral
administration. Thirteen percent of simvastatin
and 20% of pravastatin are excreted renally.
Neither compound is significantly affected by
renal dysfunction, and dosage reductions are not
necessary in patients with mild to moderate renal
insufficiency.6, 7
Statins generally are tolerated better than other
lipid-lowering drugs. However, mild, transient
gastrointestinal disturbances and muscle aches
occurred, and hepatitis, myopathy, rash,
insomnia, disturbing or vivid dreams, and
difficulty sleeping or concentrating were reported
rarely. Dysfunction of certain cranial nerves
(resulting in alteration of taste, impairment of
extraocular movement, and facial paresis),
tremor, dizziness, vertigo, memory loss,
paresthesia, peripheral neuropathy, peripheral
nerve palsy, psychiatric disturbances, anxiety,
insomnia, and depression were reported during
clinical trials.1, 5–7 Memory loss associated with
the statins is listed in the manufacturers’ product
information.6, 7, 9–12
Two clinical trials were designed to evaluate
the effect of simvastatin or pravastatin on
cognitive function. One study compared the
effects of these agents on measures of CNS
activity: electroencephalogram (EEG) evoked
potentials, mood, sleep, or cognitive performance.13
This double-blind, placebo-controlled, crossover
study randomized 25 healthy volunteers to 4
weeks each of simvastatin 40 mg, pravastatin 40
mg, and placebo in random order. Each
treatment period was followed by a 4–6-week
washout period. Cognitive function was
evaluated by the digit symbol substitution test,
and no statistically significant differences were
found between treatment groups. The study had
90% power to detect differences at the 0.05
significance level. Subjects reported significantly
greater difficulty falling asleep while receiving
simvastatin compared with pravastatin but
neither differed from placebo. The investigators
concluded that neither drug exerts significant
and pravastatin (nonformulary), along with the
other drugs in this class, are well tolerated in the
general population. Although the agents are
mevinic acid-derivatives and have similar
mechanisms of action and the same
pharmacologic effect, they have important
differences in their chemical structures, which
affects their relative lipophilicity. Simvastatin has
a methyl substituent attached to the hexahydro-
naphthalene nucleus, which increases its
lipophilicity, whereas pravastatin has a hydroxyl
substituent, which increases its hydrophilicity.8
In addition, simvastatin’s closed lactone ring
enhances its lipophilicity compared with
pravastatin, which is the only statin administered
in the hydroxy acid form. A more lipid-soluble
closed lactone HMG-CoA reductase inhibitor,
such as simvastatin, may have a greater
propensity for crossing the blood-brain barrier
and affecting CNS activity, even though only very
low levels have been found in human cerebral
spinal fluid.8 Pravastatin is the most hydrophilic
polar statin, followed in decreasing hydro-
philicity by cerivastatin and fluvastatin,
atorvastatin, lovastatin, and simvastatin.
Cerivastatin and fluvastatin are considered water
soluble. Atorvastatin is only slightly water
soluble. Lovastatin is more lipophilic, and
simvastatin, which is 194 times more lipophilic
than pravastatin, is by far the most lipophilic of
the statins.8
Pharmacokinetic variability also contributes to
the differences among the statins. After oral
administration, only about 5% and 17% of the
doses of simvastatin and pravastatin, respectively,
reach the general circulation as active drug.6, 7
This low bioavailability is due to incomplete
absorption and extensive first-pass hepatic
metabolism. Both drugs undergo extensive
hepatic metabolism. Simvastatin is an inactive
prodrug that requires hepatic activation through
hydrolysis to -hydroxyacid, an active inhibitor
of HMG-CoA reductase. Other hepatic
metabolites are 6-hydroxy, 6-hydroxymethyl, and
6-exomethylene (as well as other derivatives).
Pravastatin is inherently active and undergoes
extensive first-pass hepatic metabolism to its
primary metabolites—the 3-␣-hydroxy isomer
and the 3-␣-, 5--, and 6--trihydroxy
metabolite. Unlike simvastatin’s metabolites,
pravastatin’s metabolites are not active in the
inhibition of HMG-CoA reductase.6, 7
Simvastatin is highly protein bound (95%)
compared with pravastatin (43–55%). Both