Indian J Physiol Pharmacol 2009; 53 (1) : 73–82

STUDY OF PLASMA LEVEL OF ATORVASTATIN AND ITS

EFFECT ON LIPID PROFILE

HEEMA R. VALERA* AND BARNA GANGULY**

* Department of Clinical Pharmacy,

Institute of Science and Technology for
Advanced Studies and Research,
Vallabh Vidyanagar (Gujarat)
and
* *Department of Pharmacology,
Pramukh Swami Medical College,
Karamsad (Gujarat)
( Received on December 20, 2008 )

Abstract : Atorvastatin, being one of the most commonly used

antihyperlipidemic agents, is prescribed frequently by physicians all over
the world but only a few data is available stating its effect in different
ethnic population, more so from this part of India. The present study was
designed focusing mainly on local population and was planned to determine
plasma level of atorvastatin 10 mg and its effect on lipid profile in newly
diagnosed hyperlipidemic patients attending Medical OPD of Shri Krishna
Hospital, Karamsad (Gujarat).

Study-I was carried out in 6 healthy volunteers to determine t max after

single dose of atorvastatin 10 mg under fasting conditions, on the basis of
which Study-II was conducted in 15 patients, collecting blood samples at a
particular time (i.e t max of Study-I) after administration of atorvastatin 10
mg/day on day 1 as well as on the last day after 8 weeks of treatment. The
plasma concentrations were determined by RP-HPLC system. Atorvastatin
10 mg/day for 8 weeks with a plasma level range (7.45, 12.08) ng/mL
significantly (P<0.05) reduced all the parameters of lipid profile from the
study population. The mean decrease in HDL-C triggers a question on the
effect of atorvastatin on HDL-C, which requires further study on a larger
population of our country.

Key words : atorvastatin hyperlipidemia HDL-C

lipid profile plasma level

INTRODUCTION atherosclerotic coronary artery disease (CAD)

is one of the major causes of premature
Hyperlipidemia- a well-known risk factor death globally (1) and it is expected to be
for cardiovascular disease, especially the most important cause of mortality in

*Corresponding Author : Heema R. Valera, 6/A, Keshav Apartments, Near Memnagar Lake, Memnagar,
Ahmedabad – 380 052; Tel. No.: +91-79-27437358; E-mail: hima_rv@yahoo.co.in
74 Valera and Ganguly Indian J Physiol Pharmacol 2009; 53(1)

India by the year 2015 (2). South Asians and of the country. The present study was
particularly Asian Indians have been found planned to determine plasma level of
to have the highest mortality rate due to Atorvastatin 10 mg in newly diagnosed
CAD amongst all ethnic groups so far studied patients of hyperlipidemia attending Medicine
(3). Hyperlipidemia and medications used to OPD of Shri Krishna Hospital, Karamsad.
lower cholesterol have received generous The patients were instructed not to change
exposure from last decade and hence, as a their dietary habit throughout the treatment
result, public is aware that high cholesterol period.
is a risk factor for cardiovascular disease
(4). Patients in whom treatment with lifestyle METHODS
modifications fails should be started on lipid-
lowering agents. Patients with multiple risk The study was conducted at Shri Krishna
factors and very high cholesterol levels may Hospital, Karamsad (Gujarat, India) and the
need early intervention with drug therapy analytical analysis was carried out at
because diet therapy may not reduce LDL Sophisticated Instrumentation Centre for
cholesterol to the goal range (4). 3-Hydroxy Applied Research and Testing (SICART,
3-methylglutaryl coenzyme A (HMG CoA) Vallabh Vidyanagar, Gujarat, India). The
reductase inhibitors (statins) are widely used study protocol was approved by HREC
in the prevention of cardiovascular events (Institutional Human Research Ethics
and are generally well tolerated. These Committee of Shri Krishna Hospital,
agents are the most potent LDL-lowering Karamsad) and the statistical analysis was
drugs available and generally are preferred
carried out using SPSS software.
in patients with elevated LDL. Statins reduce
LDL by 20 to 60%, decrease triglycerides by
Participants
10 to 40%, and increase HDL by 5 to 15%
(4). Currently available products include
lovastatin, pravastatin, simvastatin, The entire study was conducted in two
fluvastatin and atorvastatin (5) which reduce subparts, Study-I and Study-II with total 21
the risk of CHD and total mortality, with participants [6 healthy, adult male
a 30% risk reduction (6). Atorvastatin, volunteers for Study-I and 15 newly
being one of the most commonly used diagnosed cases of hyperlipidemia (of either
antihyperlipidemic agents, is prescribed very sex) for Study-II].
often by physicians world wide. But there
are less available data on atorvastatin’s effect No formal sample size calculation was
on various profiles and parameters of performed for Study-I carried out on healthy
different ethnic population more so from this volunteers, as it was planned to characterize
part of world. The study was designed to only the absorption profile more specifically
focus mainly on the local population of tmax of atorvastatin 10 mg after single oral
Kramsad-Gujarat with a dietary habit of high administration, hence considering it as a
calorie content more specifically high oil pilot study, only 6 healthy male volunteers
content on the daily basis, which is different with the homogenous demographic profile
to some extent from that of the other parts were enrolled.
Indian J Physiol Pharmacol 2009; 53(1) Study of Plasma Level of Atorvatatin 75

For Study-II in patients, the sample size other drugs known to modulate lipid
was calculated on the basis of following parameters like corticosteroids and
formula : isotretinoin were excluded. Pregnant and
breast feeding women were also excluded to
Sample size n = 4pq/d 2 take part in the study. Patients were asked
not to change their eating habits during the
Where, p = expected prevalence, q = 100-p, course of the study.
d = degree of precision.
All the participants (i.e. healthy
Based on the experience of last few years, volunteers recruited for Study-I and newly
the expected prevalence (p) was considered diagnosed cases of hyperlipidemia recruited
to be 50% in a year. Hence, considering for Study-II) were treated with atorvastatin
p = 50%, q = 100-50 = 50% and d = ± 10%, from tablets 10 mg of the same batch of same
the above formula, about 100 newly diagnosed manufacturer, to avoid formulation factor
patients were expected to receive the that sometimes interferes with the study
treatment with atorvastatin yearly. result.

This was the expected prevalence of one The study was started only after study
year in such a tertiary care rural hospital protocol approval and permission from
here, and as the present study was planned institutional human research ethics
to be completed within 4 months with the committee (HREC).
patient recruitment period of 2 months only.
Hence, approximately 16 newly diagnosed Study-I : On healthy volunteers
cases of hyperlipidemia were expected in the
duration of two months. However, we could Six volunteers were screened for their
enroll 15 patients to take part in the Study- healthy status one week prior to study and
II. a written informed consent for participation
in the study was obtained from each healthy
All the participants were enrolled based volunteer after explaining them the study
on the inclusion and exclusion criteria. aspects. They were hospitalized at medicine
Patients with impaired renal or hepatic IPD of Shri Krishna Hospital, Karamsad, one
functions; diabetes mellitus type I or night prior to the day of dosing, being
uncontrolled diabetes mellitus type II; reevaluated by the physician at the time of
hypothyroidism; with the history of MI, admission for their vital signs (pulse rate,
CAD, sever or unstable angina pectoris, blood pressure and temperature). When
severe cardiac arrhythmia or clinically admitted, the volunteers received written
manifested heart failure were excluded. Also information explaining the events to be
alcoholics and patients taking other lipid carried out during the study period, with the
lowering agents, antioxidant vitamins, scheduled time for the drug administration,
immunosuppressive drugs, drugs known to meals, blood sampling and subsequent
be associated with myopathy in association discharge. The volunteers fasted overnight
with HMG Co-A reductase inhibitors and for at least 10 hours prior to dosing and
76 Valera and Ganguly Indian J Physiol Pharmacol 2009; 53(1)

lunch was provided 4 hours post-dose. A administered. The blood samples from
single oral dose of Atorvastatin tablets 10 each patient were withdrawn at tmax
mg was administered to each volunteer with obtained from Study-I after administration
approximately 240 ml of water. They were of drug for determination of plasma drug
informed to remain in sitting position for concentration.
first 3 hours after dosing and also advised to
avoid severe physical exertion throughout On visit 2 (8 weeks after visit 1) : Detailed
the confinement period. history of patients, drug intake and event of
any adverse drug reaction were reported. All
Atorvastatin is rapidly absorbed after oral the patients were instructed to visit the
administration with peak plasma O.P.D after an over night fast of at least 10
concentrations within 1-2 hours (24), hence, hours and the last dose of drug was
to characterize only the absorption profile administered to each patient and blood
of atorvastatin, the blood samples were samples were collected at tmax obtained
collected 30 minutes prior to drug from Study-I. All the investigations including
administration (pre-dose) and at 0.5, 1.0, 1.5, estimation of lipid profile, recording of
2.0, 2.5, 3.0 and 6.0 hours post-dose vital signs and ECG were carried out after
administration. 8 weeks of treatment with atorvastatin
tablets 10 mg.
Study-II : On newly diagnosed patients of
hyperlipidemia Out of 15 patients, 1 patient was dropped
out because of his failure to come for routine
On Visit 1 (Day 0): A detailed history of follow-up visit.
the O.P.D. patients was taken with special
reference to history of drug intake and Blood sample collection, plasma separation and
allergy. The baseline investigations including its handling prior to analysis
lipid profile, ECG and recording of vital signs
were carried out on O.P.D. basis. Blood samples from all the participants
were collected in BD Vacutainer (Lithium
Baseline reports of all the investigations Heparin 68 USP units) and immediately
were collected and the newly diagnosed centrifuged at 4000 rpm for 10 minutes under
hyperlipidemic patients were prescribed with cooling conditions to separate supernatant
Atorvastatin tablets 10 mg/day by physician. plasma. Separated plasma samples were
Also, the patients were explained the study collected with the help of micropipette in
aspect and asked for their willingness to RIA vials previously labeled and then stored
participate. Written informed consent for at –40°C until analyzed.
participation was obtained from each patient
willing to take part in the study. On day 1 Analysis of Atorvastatin
(i.e. the first day of drug administration);
the patients were asked to report to the Plasma sample analysis was performed
O.P.D. after an over night fast of at least 10 by a validated high performance liquid
hours and the first dose of drug was chromatography (HPLC) with UV- detection.
Indian J Physiol Pharmacol 2009; 53(1) Study of Plasma Level of Atorvatatin 77

The HPLC conditions were optimized to RESULTS

obtain an adequate separation of the eluted
compound by the use of C-18 prontosil Study I: On healthy volunteers
column, mobile phase containing methanol :
acetonitrile : water (45 : 45 : 10 v/v/v) and Plasma level of atorvastatin in healthy
1.0 ml/min flow rate. Ibuprofen was applied volunteers :
as an internal standard, neutralizing the
error inherent in sample injection; After single dose administration of
eliminating random errors. The optimum Atorvastatin 10 mg tablet to 6 healthy
wavelength for detection was 240 nm at male volunteers, the peak plasma level (C max ,
which much better detector response for mean ± SD) of 14.04 ± 2.26 ng/ml was
drug was obtained. achieved at the peak time (tmax, median) of
1.5 hours. AUC 0–6 (mean ± SD) was found to
Clinical laboratory measurement of parameters be 45.38 ± 9.30 ng.hr/ml calculated using
of lipid profile
trapezoidal formula.

Triglyceride reagent (GPO-ADPS), Study II : On newly diagnosed patients of

cholesterol reagent (CHOD-PAP) and HDL- hyperlipidemia
cholesterol reagents (by immunoinhibition)
are intended for in-vitro quantitative Evaluation of plasma concentration of
determination of triglyceride, cholesterol and Atorvastatin 10 mg in hyperlipidemic
HDL-C determination respectively in human patients :
serum.
As per the results obtained from Study-
Statistical Analysis I on healthy volunteers, the blood samples
from hyperlipidemic patients were collected
Data handling and statistical analysis at 1.5 hour after administration of one tablet
were carried out using Microsoft Excel and of atorvastatin 10 mg on day 1 as well as on
SPSS software. last day i.e. after 8 weeks of treatment; to
determine plasma concentrations as shown
Student’s t-test for paired variables was in Table I.
used to compare the differences between
lipid parameters at baseline and after 8 Evaluation of lipid profile in hyperlipidemic
weeks treatment period. patients :

Linear regressions were used to Lipid profile including Total serum

determine the relationship between cholesterol (TC), Triglycerides, HDL-C, LDL-
parameters of lipid profile (i.e. % change C, VLDL-C, TC/HDL-C and LDL-C/HDL-C
from baseline) and plasma concentration of were evaluated before starting the treatment
Atorvastatin 10 mg after 8 weeks of and after 8 weeks of treatment. Table II and
treatment. Fig. 1 show the value of parameters of lipid
78 Valera and Ganguly Indian J Physiol Pharmacol 2009; 53(1)

TABLE I : The plasma concentration of Atorvastatin DISCUSSION

10 mg in hyperlipidemic patients after first
dose (on day 1) and after 8 weeks of
treatment; at 1.5 hour following drug intake. Present study involves the data of 6
healthy male volunteers and total 14 patients
Concentration, Concentration,
ng/ml (at 1.5 ng/ml (after 8 (5 male and 9 female newly diagnosed cases
Patient hours after weeks, at 1.5 of hyperlipidemia).
number administration hours after
of first dose, administration
on day 1) of dose) In this study, all the participants were
1 8.42 11.26
treated with Atorvastatin Tablets 10 mg/day;
2 0.33 8.5 of the same brand and from the same batch
3 3.14 10.19
4 1.68 7.45 to avoid formulation factor that sometimes
5 5.13 9.66 interferes with the results.
6 2.25 10.43
7 8.85 10.83
8 0.98 9.03 The time (tmax) required to achieve
9 4.93 10.19
10 4.39 12.08 m a x i m u m p l a s m a c o n c e n t r a t i o n ( C max) o f
11 2.09 8.59
12 3.25 9.14 Atorvastatin 10 mg was considered as 1.5
13 8.36 12.05 hours as obtained form the results of Study-
14 6.06 11.72
Mean±SD 4.28±2.82 10.05±1.46 I on healthy volunteers and on the basis of
which, blood samples were collected from 14
Note : Patient No. 15 was dropped out from the hyperlipidemic patients to determine plasma
study, as he was not able to arrive for routine
follow-up. concentrations of atorvastatin at 1.5 hour
after first intake of Atorvastatin Tablets 10
T A B L E I I : Effect of Atorvastatin 10 mg on LIPID mg as well as after 8 weeks treatment
PROFILE (mean±SEM). period. As shown in Table I, plasma
concentration (mean ± SD) for patients on day
Before After 8 % Reduction
Lipid treatment weeks from baseline 1 at 1.5 hours after first intake of
profile (mg/dl) treatment after 8 weeks Atorvastatin Tablets 10 mg was 4.28 ± 2.82
(i.e. baseline) (mg/dl) of treatment
ng/ml (range: 0.33, 8.52) and after 8 weeks,
Total 223.09± 8.92 142.67± 7.07 35.95± 2.17 it was found to be 10.05 ± 1.46 ng/ml (range:
cholesterol
7.45, 12.08). A high degree of inter-subject
Serum 178.43± 29.88 103.87± 12.97 35.98± 4.76
triglyceride variability observed in Cmax in this study is
HDL-C 50.82± 2.44 45.92± 2.19 8.90± 3.01 noteworthy, which may be due to age,
LDL-C 136.41± 6.38 77.39± 6.36 42.97± 4.23
VLDL-C 35.69± 5.98 20.80± 2.59 35.82± 4.83 gender, food intake, presence of concomitant
TC/HDL-C 4.49± 0.25 3.22± 0.23 28.66± 3.29 disease and drug therapy, level of CYP3A4
LDL-C/HDL-C 2.73± 0.16 1.79± 0.18 36.21± 5.32 expression and activity and all the factors
which influence the body’s handling of
profile before treatment (i.e. baseline), after atorvastatin (7). An important characteristic
treatment and % reduction from baseline of CYP3A4 is the large inter-individual
after treatment. Fig. 2 shows relationship variability in activity (about 5-fold), which
between parameters of lipid profile (i.e. % reflects genetic polymorphism combined with
change or decrease from baseline) and plasma modulation by environmental factors (8).
concentration of Atorvastatin 10 mg after 8 Intake of known strong inhibitors or inducers
weeks of treatment. of CYP3A4 did not occur in this study.
Indian J Physiol Pharmacol 2009; 53(1) Study of Plasma Level of Atorvatatin 79

Fig. 1 : Mean value of parameters of lipid profile before treatment (i.e.

baseline) and after treatment with Atorvastatin 10 mg for 8 weeks.
80 Valera and Ganguly Indian J Physiol Pharmacol 2009; 53(1)

Fig. 2 : Relationship between parameters of lipid profile (i.e. % change from baseline)
and plasma concentration of Atorvastatin 10 mg after 8 weeks of treatment.
Indian J Physiol Pharmacol 2009; 53(1) Study of Plasma Level of Atorvatatin 81

It is evident that there was no adverse 21). For example, in clinical studies
event by any of the participant during the comparing high therapeutic doses of
course of the study. Patients’ vital signs (B.P. atorvastatin (20 and 40 mg) and simvastatin
and Pulse rate) were recorded during each (40 and 80 mg) in hypercholesterolemic
visit and ECGs were performed before subjects, atorvastatin produced a smaller
and after treatment and no significant increase in HDL cholesterol and apoA-I than
abnormality was found throughout the simvastatin at corresponding drug doses (16,
treatment period. 17). It was also found in previous studies
that atorvastatin also demonstrated a
As shown in Table II and Fig. 1 (A) to significantly attenuated increase in HDL
(G), 8 weeks’ treatment with Atorvastatin cholesterol compared with the new HMG-CoA
Tablets 10 mg/day significantly (P<0.05) reductase inhibitor rosuvastatin at low doses
reduced the mean values of all the (3% HDL apoA-I elevation with 10 mg
parameters of lipid profile i.e. serum atorvastatin versus 7% HDL apoA-I elevation
cholesterol, serum triglycerides, HDL-C, with 10 and 5 mg rosuvastatin) (22). It is
LDL-C, VLDL-C, TC/HDL-C ratio and revealed that HDL cholesterol reduction
LDL-C/HDL-C ratio from the respective after high-dose atorvastatin is an early and
baselines. transient event in HFH patients which
magnitude depends on the presence of a
In the present study, the changes in all residual LDL-R activity ((23). In the present
the parameters of lipid profile were as per study, it has been observed that even a
the previous studies (9, 10, 11, 12) except a smaller dose i.e. 10 mg atorvastafin daily
significant reduction (P<0.05) in HDL-C level for 8 weeks significantly reduced HDL-C from
after 8 weeks of treatment with Atorvastatin baseline in the patients from Karamsad-
10 mg. However, 4 patients out of 14 patients Gujarat. Although after the treatment
in this study, showed a slight increase in period, all the other parameters were well
HDL-C level which was non-significant within the target normal range in the
(P>0.05). More recently, the importance of majority of patients, the significant decrease
drug therapy on HDL-C metabolism has been in HDL-C level pointing towards further dose
recognized (14). Numerous studies have reduction to 5 mg atorvastatin on daily basis,
identified HDL cholesterol and its major in this population.
protein component, apolipoprotein A-I (apoA-
I), as having a direct protective role against In present study, as per the published data
the development of CAD (14, 15). There has (13) we could not conclude any correlation
been tremendous interest in the effect of between plasma atorvastatin c o n c e n t r a t i o n
HMG-CoA reductase inhibitors on HDL-C and subsequent mean reduction in all the
metabolism, with reports that the various parameters of lipid profile [Fig 2 (A) to (D)].
agents in this class appear to have Moreover, a significant reduction (P<0.05)
quantitatively different effects on HDL-C in HDL-C level a triggers a question on
levels (11, 16, 17). Atorvastatin, in contrast beneficial effect of atorvastatin on HDL-C.
to some other statins, appears to lose its To explain this, a detailed study on a larger
HDL-raising effect at higher doses (11, 16, population of our country is necessary.
82 Valera and Ganguly Indian J Physiol Pharmacol 2009; 53(1)

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