International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 No.

8/2010 (497-503)

Non-concurrent dosing attenuates the

pharmacokinetic interaction between
amlodipine and simvastatin
Original C.G. Park1, H. Lee2*, J.W. Choi3, S.J. Lee4, S.H. Kim1 and H.E. Lim1
2010 Dustri-Verlag Dr. K. Feistle
ISSN 0946-1965 1CardiovascularCenter, Guro Hospital, Korea University, Seoul, South Korea,
2UC Washington Center for Drug Development Science, Department of
Biopharmaceutical Sciences, School of Pharmacy, University of California,
Washington, DC, USA, 3R&D Center, Hanall Pharmaceutical Co., Ltd., Gyeonggi-do
and 4R&D Center, Hanall Pharmaceutical Co., Ltd., Daejeon, South Korea

Attenuated drug interaction by non-concurrent dosing

Key words Abstract. Objectives: To explore if non-
non-concurrent dosing concurrent amlodipine dosing results in less
amlodipine simvastatin drug interaction, the pharmacokinetic pro-
drug interaction files, safety and efficacy endpoints were as-
cytochrome P-450
sessed following repeated doses of simva-
statin, co-administered concurrently or non-
concurrently with amlodipine in patients with
coexisting hypertension and hyperlipidemia.
*This author contributed
equally to this work.
Methods: Seventeen patients randomly re-
ceived daily doses of 20 mg simvastatin and
5 mg amlodipine for 6 weeks, either with both
drugs at 7:00 PM (concurrent) or with simva-
statin at 7:00 PM followed by amlodipine at
11:00 PM (non-concurrent). The maximum
plasma concentration (Cmax) and the area un-
der the concentration-time curve up to the last
quantifiable concentration (AUClast) were es-
timated at steady state. Lipid profiles and
blood pressure values were also compared
between the concurrent and non-concurrent
groups. Results: The Cmax and AUClast and of
Received simvastatin acid in the non-concurrent amlo-
December 7, 2009; dipine dosing group were 63.2% and 66.0%,
accepted respectively, of the values obtained in the
February 24, 2010 concurrent group (1.2 1.0 vs. 1.9 0.9
ng/ml and 10.3 8.3 vs. 15.6 7.5 h ng/ml,
Correspondence to respectively, mean standard deviation).
H. Lee, MD, PhD Changes from baseline in lipid profile and
Associate Adjunct
blood pressure were comparable between the
Professor, Director groups. Conclusions: Non-concurrent dosing
Center for Drug
may be a useful and safe therapeutic option
Development Science,
for patients who require two or more drugs
Department of Bio-
pharmaceutical
administered concomitantly, but who are
Sciences, School of likely to develop unwanted drug interactions.
Pharmacy, University
of California,
San Francisco, UC
Washington Center, Introduction
1608 Rhode Island
Avenue, NW, Hypertension and hyperlipidemia often
Washington, DC 20036,
coexist, rendering combination of two or more
USA
Howard.Lee@ucsf.edu drugs a rational treatment option. However,
leehwd@gmail.com co-administration of more than one drug at
the same time places patients at a risk for drug
interaction, which can be sometimes fatal.
Drug interaction is more likely to occur when
a drug inhibits the enzyme that metabolizes a
co-administered drug or two drugs compete
for the same metabolizing enzyme.
The latter is the case for simvastatin and am-
lodipine, both of which involve the cyto-
chrome P-450 (CYP) 3A4 as the main drug me-
tabolizing enzyme [9, 24]. For example, when
simvastatin was combined with amlodipine, the
biological activity of simvastatin, as measured
by the peak concentration and the area under
the concentration-time curve of 3-hydroxy-
3-methylglutaryl-coenzyme A (HMG-CoA)
reductase inhibitors, increased by 42.7%
(p < 0.05) and 26.7% (p < 0.05), respectively
[20].
Simvastatin is an inactive lactone pro-
drug, undergoing hydrolysis by plasma ester-
ases (i.e., non-CYP process) to active simvas-
tatin acid to exert its lipid-lowering effect
[24]. Simvastatin acid has the greatest inhibi-
tory effect on the HMG-CoA reductase com-
pared to the other active CYP3A4 downstream
metabolites [8], and is further metabolized
mainly by CYP3A4 (i.e., 80%) and, to some
extent, by CYP2C8 as well [21]. CYP3A4 in-
hibitors reduce the presystemic metabolism
of simvastatin more than the systemic metab-
olism, leading to increased plasma concentra-
tions of both simvastatin and simvastatin acid
[19]. Amlodipine, unlike verapamil or diltia-
zem, does not significantly inhibit CYP3A4
in humans [14, 18, 19]. Therefore, in the pre-
vious example by Nishio et al. [20] it is most
likely the increased plasma concentrations of
Park, Lee, Choi et al.
simvastatin acid with some contributions from
the downstream active metabolites that aug-
mented biological activity of simvastatin al-
though the actual mechanism is unclear.
When a combination of simvastatin and
amlodipine is indicated, one option may be to
take amlodipine several hours later after the
time of simvastatin dosing. This non-concur-
rent dosing regimen is sensible because later
presentation of amlodipine to the liver and, to
some extent, the gut, may enable more effi-
cient metabolism of simvastatin without in-
terference from co-administered amlodipine.
Based on this understanding, it was hypo-
thesized that non-concurrent dosing of amlo-
dipine may result in a reduced plasma level of
simvastatin acid, compared to concurrent (i.e.,
simultaneous) administration. The objective
of the present study was to compare the phar-
macokinetic profiles of simvastatin acid fol-
lowing repeated doses of simvastatin, co-ad-
ministered with amlodipine concurrently or
non-concurrently, in comorbid hypertensive
and hyperlipidemic patients. In addition, sev-
eral pharmacodynamic endpoints such as bl-
ood pressure and lipid profile were compared
between the different dosing regimens of am-
lodipine.
Methods
Subjects
Patients with coexisting hypertension and
hyperlipidemia, aged 30 75 years, were
screened after a 1-week drug wash-out period,
which was extended to 2 weeks in case of
amlodipine because of its long half-life. The
sitting morning systolic (SitSBP) and dia-
stolic (SitDBP) blood pressure of eligible pa-
tients, measured at the screening and study
initiation visits, fell in the ranges of 140 179
mmHg and 90 114 mmHg, respectively.
Fasting blood low density lipoprotein (LDL)
cholesterol level was also assessed, and
should be 125 mg/dl. Patients with hyper-
tension or hyperlipidemia of a secondary na-
ture, past medical history of stroke or myocar-
dial infarction, symptomatic arrhythmia or
unstable angina, were excluded. This study
was approved by the Korea University Insti-
tutional Review Board and conducted ac-
cording to the current Good Clinical Practices
498
and other applicable laws and regulatory re-
quirements in Korea, which conform to both
the Declaration of Helsinki and other interna-
tional ethical standards.
Study design and treatments
This was a randomized, parallel, open-la-
bel study designed to compare the pharma-
cokinetic profiles of simvastatin acid and vari-
ous pharmacodynamic endpoints between two
amlodipine dosing regimens. Eligible patients
randomly received daily oral doses of 20 mg
simvastatin (Zocor) and 5 mg of amlodipine
(Norvasc), purchased in the open market, for
6 weeks based on one of the following sched-
ules: 1) simvastatin and amlodipine at 7:00
PM (i.e., concurrent administration), or 2) sim-
vastatin at 7:00 PM, followed by amlodipine at
11:00 PM (i.e., non-concurrent administra-
tion). To increase drug compliance, a drug
diary was distributed and patients were asked
to record actual date and time of drug intake,
followed by a weekly telephonic interview.
Other antihypertensive agents, lipid low-
ering drugs, and drugs that can affect CYP
3A4 activity (e.g., ketoconazole, itracona-
zole, erythromycin, clarithromycin, and pro-
tease inhibitors) were not allowed during the
study. In addition, patients were instructed
not to take any food or beverages containing
grapefruit or pomelo at least within 1 week of
study commencement and during the study.
Pharmacokinetic sampling and
assay
Subjects were instructed to take the as-
signed medications at the scheduled times as
closely as possible during the study and ad-
mitted to the clinic on Day 42 around 5:00 PM,
having an intravenous line inserted for phar-
macokinetic plasma sampling. A regular meal
was then provided, and the assigned medica-
tions were administered under the supervi-
sion of the study personnel. Pharmacokinetic
samples were obtained at 0 (i.e., pre-dose), 2,
3, 4, 6, 8, 10, and 15 h post simvastatin dose.
Patients were discharged in the morning of
the next day.
Plasma concentrations of simvastatin,
simvastatin acid, and amlodipine were as-
Attenuated drug interaction by non-concurrent dosing
sessed using the validated LC/MS/MS meth-
ods [4, 17], which covered 0.1 20.0 ng/ml
(simvastatin), 0.1 2.0 ng/ml (simvastatin
acid), and 0.5 40.0 ng/ml (amlodipine), re-
spectively. The inter- and intra-assay coeffi-
cients of variation were less than 11.2%. In
addition, the accuracy of the inter- and intra-
assay ranged between 88.2 and 109.7%.
Safety and efficacy assessments
Clinical and laboratory evaluations in-
cluding SitSBP and SitDBP measurements,
EKG, hematology, blood chemistry including
lipids profile, and urinalysis were measured
at baseline and Week 6. In addition, compre-
hensive safety assessments, including physi-
cal examinations and monitoring of adverse
events, were performed throughout the study.
Patients were removed from the study if their
SitSBP or SitDBP values were 180 or 115
mmHg, respectively.
Pharmacokinetic analysis
The following pharmacokinetic parame-
ters were estimated from the plasma concen-
trations of simvastatin and simvastatin acid:
Cmax (the maximum plasma concentration),
tmax (the time at which Cmax occurs), and
AUClast (the area under the plasma concentra-
tion-time curve to the last quantifiable con-
centration). Since amlodipine was adminis-
tered concurrently or non-concurrently with
simvastatin depending on the dosing sched-
ule, AUClast and partial AUC, i.e., AUC04
(AUC up to 4 h post dose of simvastatin) were
estimated to assess the effect of the initial ex-
posure by amlodipine. WinNonlin Pro-
fessional (version 5.2.1, Pharsight Corp.,
Mountain View, CA, USA) was used and AUC
was estimated by the linear trapezoidal method.
Statistical analysis
Descriptive statistics (e.g., mean and stan-
dard deviation for continuous variables, fre-
quency and percentage for categorical vari-
ables) were used to summarize data. Changes
from baseline at Week 6 in SitSBP and LDL
cholesterol were primary efficacy endpoints,
499
which were compared between the concur-
rent and non-concurrent amlodipine dosing
groups. Changes from baseline in SitDBP,
fasting total cholesterol, high density lipopro-
tein (HDL) cholesterol and triglyceride were
also evaluated. The frequency of adverse
events and number of subjects experiencing
them were summarized by preferred term and
body system in each amlodipine dose group.
The two sample t-test and c2-test were used
for continuous and categorical variables, re-
spectively, using SAS (version 9.1.3, SAS In-
stitute Inc., Cary, NC, USA). A two-tailed
p value of 0.05 or less was regarded as statisti-
cally significant, and no correction for the
multiple comparisons was made due to the
exploratory nature of this study.
Results
Subjects and baseline
characteristics
A total of 17 subjects, aged 42 74, were
randomly assigned to either the concurrent
(n = 9) or non-concurrent (n = 8) amlodipine
dosing group (Table 1). One subject from the
non-concurrent group dropped out from the
study because of protocol violation. In addi-
tion, 1 subject from the concurrent group did
not take the assigned medication just prior to
the pharmacokinetic sampling on Day 42, and
was therefore removed from the pharmaco-
kinetic analysis dataset. Approximately, 60%
were female subjects, and there was no statis-
tically significant difference between the con-
current and non-concurrent amlodipine dos-
ing groups for blood pressure and lipid profile
values.
Pharmacokinetic analysis
Table 2 summarizes the pharmacokinetic
parameters of simvastatin, simvastatin acid,
and amlodipine. Though not statistically sig-
nificant, the Cmax and AUClast of simvastatin
acid in the non-concurrent amlodipine dosing
group were numerically lower than those in
the concurrent dosing group (1.2 1.0 vs. 1.9
0.9 ng/ml and 10.3 8.3 vs. 15.6 7.5 h
ng/ml, respectively, mean standard devia-
 Park, Lee, Choi et al. 500

Table 1. Baseline characteristicsa.

Efficacy and safety analysis

Changes from baseline for various effi-

Variable Simvastatin plus amlodipine dosing
cacy variables are summarized in Table 3. Af-
Concurrent (n = 9) Non-concurrent (n = 8)
ter 6 weeks of treatment, there were no statis-
Age (years) 54.2 4.5 56.6 9.7 tically significant differences between the
Female (n, %) 5 (55.6) 5 (62.5) concurrent and non-concurrent amlodipine
Body weight (kg) 71.3 13.6 66.6 14.6 dosing groups in the changes from baseline
Total cholesterol (mg/dl) 239.1 52.9 225.4 25.9
for total cholesterol, LDL cholesterol, triglyc-
eride, SitSBP, and SitDBP.
LDL cholesterol (mg/dl) 161.3 43.1 151.0 14.4
A case of fatigue and cough (concurrent)
HDL cholesterol (mg/dl) 48.2 13.6 59.1 17.5 and diarrhea (non-concurrent) were reported,
Triglyceride (mg/dl) 150.4 57.3 157.8 91.1 respectively, but none of these occurrences
SitSBP (mmHg) 149.9 5.9 148.9 6.1 was considered as causally associated with
SitDBP (mmHg) 95.2 2.8 97.0 5.8 the assigned medication(s).

aMean standard deviation and frequency (%) are shown for continuous and
categorical variables, respectively. None of the variables were statistically sig-
nificant (i.e., p > 0.05) when compared between the concurrent and non-concur-
rent amlodipine dosing groups. SitSBP = sitting systolic blood pressure, SitDBP
= sitting diastolic blood pressure, LDL = low density lipoprotein, HDL = high density
lipoprotein.
Figure 1. Mean plasma concentration-time pro-
files of simvastatin (left panel) and simvastatin acid
(right panel) on Day 42 for concurrent () and non-
concurrent (l) dosing of amlodipine. Error bars
represent the standard deviation at each sampling
time.
tion). This reduced systemic level of simva-
statin acid in the non-concurrent amlodipine
dosing group is clearly shown in Figure 1
(right panel). In addition, the tmax of sim-
vastatin acid in the concurrent amlodipine
dosing group was delayed by 2.1 h.
Discussion
The key finding of the present study is that
the non-concurrent administration of amlo-
dipine (i.e., 4 h after simvastatin) resulted in a
numerically lower systemic level of simvas-
tatin acid while the efficacy of statin appeared
to be maintained. The Cmax and AUClast and
of simvastatin acid in the non-concurrent
amlodipine dosing group were 63.2% and
66.0%, respectively, of the values obtained in
the concurrent group (Table 2) (Figure 1), but
the changes in lipid profiles from baseline
were comparable between different amlodi-
pine dosing groups after 6 weeks of simvasta-
tin treatment (Table 3).
It is also interesting to note that the
AUClast and AUC04 for amlodipine were
similar between the concurrent and the non-
concurrent amlodipine dosing groups (Table
2). This observation may reflect amlodipines
flat (i.e., less fluctuating) pharmacokinetic
profile at steady state due to its long half-life
[25]. Therefore, the systemic level of amlo-
dipine during the post-absorption phase is un-
likely to be the mechanism for the different
levels of simvastatin acid shown in the pres-
ent study.
The selective increases in the AUClast and
Cmax of simvastatin acid seen in the present
study support the notion that amlodipine does
not significantly inhibit CYP3A4. If amlo-
dipine inhibited CYP3A4 in the concurrent
dosing group, which did not occur or was mit-
igated in the non-concurrent group, both
lactone and acid forms of simvastatin would
have reduced in the latter group. For example,
 Attenuated drug interaction by non-concurrent dosing 501

Table 2. Pharmacokinetic parametersa for simvastatin, simvastatin acid, and amlodipine.

Simvastatin plus Simvastatin Simvastatin acid Amlodipine

amlodipine
Cmax tmax (h) AUClast Cmax tmax (h) AUClast AUClast AUC04
dosing
(ng/ml) (h ng/ml) (ng/ml) (h ng/ml) (h ng/ml) (h ng/ml)
Concurrent 4.3 2.2 3.0 0.8 18.0 7.8 1.9 0.9 7.0 1.5 15.6 7.5 107.4 20.3 29.6 5.4
(n = 8)
Non-concurrent 4.5 1.8 2.9 1.6 19.9 8.2 1.2 1.0 4.9 2.8 10.3 8.3 111.6 17.6 30.0 7.2
(n = 7)

aMean standard deviation are shown. None of the variables were statistically significant (i.e., p > 0.05) when compared between the
concurrent and non-concurrent amlodipine dosing groups.

simvastatin [19]. In this case, hydrophilic

Table 3. Change from baseline on Day 42 for efficacy variablesa.
Variable Simvastatin plus amlodipine dosing
Concurrent (n = 9) Non-concurrent (n = 7)
Total cholesterol (mg/dl) 74.7 26.2 66.7 7.6
LDL cholesterol (mg/dl) 66.9 17.3 64.9 6.7
HDL cholesterol (mg/dl) 2.4 7.9 0.3 9.8
Triglyceride (mg/dl) 7.0 51.6 27.7 64.3
SitSBP (mmHg)b 25.1 12.2 31.4 9.0
SitDBP (mmHg)b 16.4 7.8 21.4 6.0
aMean standard deviation is shown and minus sign () represents decrease
from baseline. SitSBP = sitting systolic blood pressure, SitDBP = sitting diastolic
blood pressure, LDL = low density lipoprotein, HDL = high density lipoprotein.
None of the variables were statistically significant (i.e., p > 0.05) when compared
between the concurrent and nonconcurrent amlodipine dosing groups. bMea-
sured in the morning approximately around 8:00 AM.
verapamil and diltiazem, calcium-channel
blocking agents known to inhibit CYP3A4,
increased both lactone and acid forms of sim-
vastatin [13, 16]. In addition, our finding ap-
pears to be in accordance with the increased
biological activity of simvastatin adminis-
tered concurrently with amlodipine [20], in
which simvastatin acid is most likely to be
what drove the increased activity of HMG-
CoA reductase inhibition.
Yet it is unclear how concurrently admin-
istered amlodipine resulted in a selective in-
crease in the plasma concentrations of sim-
vastatin acid compared to non-concurrent
dosing while plasma simvastatin levels were
similar. However, a couple of hypothetical
mechanisms can be proposed. First, amlo-
dipine might have inhibited the activity of
OATP1B1, which plays an important role in
the hepatic uptake of most statins including
simvastatin acid will be more easily affected
by the inhibition of OATP1B1 than simva-
statin, which is a lipophilic lactone, resulting
in a selective increase in the plasma concen-
trations of simvastatin acid. A similar mecha-
nism has been reported for gemfibrozil, which
inhibits OATP1B1-mediated hepatic uptake
[23], but not CYP3A4 [2]. For example,
gemfibrozil increased the AUC of simvasta-
tin acid by 185% while the AUC of simvasta-
tin was practically unchanged [1].
Since simvastatin acid is metabolized
partly by CYP2C8 [21], plasma concentra-
tions of simvastatin acid can be selectively in-
creased if amlodipine inhibits CYP2C8. How-
ever, its effect will be limited because
CYP3A4 is still the primary (i.e., 80%) me-
tabolizing enzyme for simvastatin acid [21].
Saturated first-pass extraction of simva-
statin in the liver during the absorption phase
may be another mechanism for the selective
increases in the AUClast and Cmax of simva-
statin acid. Sufficiently high concentrations
of amlodipine in the liver during the absorp-
tion phase can accelerate the temporary sat-
uration of CYP3A4 [3]. Simvastatin lactone is
metabolized by CYP enzymes much faster
than simvastatin acid since the intrinsic clear-
ance of the lactone form is almost 70 times
higher than that of the acid form [6]. There-
fore, simvastatin acid will be affected by satu-
rated CYP3A4 more than simvastatin, lead-
ing to a disproportionate increase in plasma
concentrations. The finding in the present
study that the tmax of simvastatin acid was de-
layed by 2.1 h in the concurrent amlodipine
dosing group also supports this proposed mech-
anism. Non-concurrent amlodipine can also
saturate the first-pass extraction by CYP3A4,
Park, Lee, Choi et al.
but this occurs only after the majority of the
dosed simvastatin has already been absorbed,
giving the drug sufficient time to be effec-
tively metabolized.
Whatever the mechanism might be, the re-
sults of the present study have several impor-
tant clinical implications. HMG-CoA reduc-
tase inhibitors, collectively known as statins,
can cause serious adverse drug reactions such
as elevation in liver enzymes and various
forms of myopathy [10]. Since simvastatin
acid has the greatest inhibitory effect on the
HMG-CoA reductase compared to the other
active CYP3A4 downstream metabolites, sim-
vastatin acid may be the major, if not the only,
moiety responsible for adverse drug reactions
by simvastatin.
Therefore, the increased systemic levels
of simvastatin acid following a combined
treatment with amlodipine is likely to increase
the risk of harmful side effects of simvastatin
[5]. However, it may be possible to reduce the
likelihood of this kind of drug interaction, at
least from the pharmacokinetic perspective,
by staggering the administration times of each
drug, as exemplified in the present study.
Previously, staggered or non-concurrent
administrations of the antiulcer agent sucral-
fate with the quinolone antimicrobials such as
norfloxacin/ofloxacin [15] and sparfloxacin
[12] were investigated. By administering the
quinolone antimicrobials 2 h (norfloxa-
cin/ofloxacin) or 4 h (sparfloxacin) before
sucralfate, the oral bioavailability of the
quinolone antimicrobials were comparable to
that seen with the quinolones administered
alone. In addition, a study in dogs reported a
mitigated pharmacokinetic drug interaction
between midazolam and diltiazem when dilti-
azem was administered at least 1 h after
midazolam [22]. Midazolam is regarded as
the most sensitive substrate of CYP3A4 [7],
and diltiazem is one of the strong inhibitors
of CYP3A4 [11]. Thus, the preventability of
pharmacokinetic drug interaction by non-con-
current dosing might have been unduly em-
phasized in this study. Similarly, only a single
administration of midazolam and diltiazem
was examined, leaving an important question
unanswered; whether the reduced pharmaco-
kinetic drug interaction by non-concurrent
dosing could be reproduced after multiple
doses even when neither drug is a sensitive
substrate or a strong inhibitor of certain drug
502
metabolizing enzymes. We strongly believe
that the present study has answered this criti-
cal question.
The present study does have some draw-
backs, one of which is its parallel design. The
direction and extent of pharmacokinetic drug
interaction can be best evaluated using the
crossover design, in which each subject serves
as his or her own control. However, we also
wanted to examine pharmacodynamic inter-
action, in which long-term follow-up for each
individual is a mandate, rendering the parallel
design logistically more feasible and practi-
cal. Another drawback of the present study is
the fact that it did not have groups adminis-
tered simvastatin or amlodipine only. How-
ever, because eligible patients had to have co-
existing hypertension and hyperlipidemia,
treatment only for one condition was not con-
sidered ethically appropriate. Its small sam-
ple size, mainly due to the exploratory nature
of the present study, is another limitation.
Based on this concern, we estimated the post
hoc power to detect the observed difference in
the logarithm transformed Cmax and AUClast
of simvastatin acid between amlodipine dos-
ing groups, with a two-tailed a error of 0.05.
33% and 35.4% were the post hoc powers for
Cmax and AUClast, respectively, which means
the present study was underpowered. All of
these issues, except for the evaluation of phar-
macodynamic interaction, can be addressed in
a pharmacokinetic drug interaction study in
healthy volunteers or patients with mild hy-
pertension using a full randomized crossover
design, in which simvastatin only, amlodipine
only, concurrent and non-concurrent amlodip-
ine and simvastatin groups are examined.
This study has been planned and will be car-
ried out shortly.
In conclusion, the non-concurrent ad-
ministration of amlodipine with regard to
the dosing time of simvastatin resulted in
less pharmacokinetic drug interaction between
amlodipine and simvastatin, which may lead
to an improved safety profile compared to
concurrent dosing regimen. Non-concurrent
dosing may be a useful and safe therapeutic
option for patients who require two or more
drugs administered concomitantly, but who
are likely to develop unwanted drug interac-
tions.
 Attenuated drug interaction by non-concurrent dosing
Acknowledgment
The authors want to thank Hanall Phar-
maceuticals Inc., Seoul, South Korea for a
grant to conduct the present study.
Source of funding and
institutions involved in the
work
The present study was funded by a re-
search grant from Hanall Pharmaceuticals,
Inc., South Korea and was conducted in the
Cardiovascular Center, Guro Hospital, Korea
University, Seoul, South Korea.
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