병원약사회지(2016), 제 33 권 제 1 호

J. Kor. Soc. Health-Syst. Pharm., Vol. 33, No. 1, 49 ~ 60 (2016)

Original Article

Nifedipine과 Gliclazide와의 약동학적 상호작용

임태환a, 김양우b, 최인a�

조선대학교병원 약제부a, 한국보건복지인력개발원b

Pharmacokinetic Drug Interaction between Nifedipine and

Gliclazide

Tae-Hwan Lima, Yang-Woo Kimb, In Choea�

Department of Pharmacy, Chosun University Hospital, 365 Pilmundaero, Dong-gu, Gwangju 501-759, Koreaa,
Korea Human Resource Development Institute for Health & Welfare, Cheongju-si, Chungbuk, Koreab

Abstract : Gliclazide and nifedipine have been clinically prescribed for the prevention or treatment
of cardiovascular diseases with diabetes. However, these drugs have potential interaction. The pur-
pose of this study was to investigate the possible effects of gliclazide on the pharmacokinetics of
nifedipine and its main metabolite, dehydronifedipine, in rats.
We evaluated the effect of gliclazide on the activity of P-glycoprotein (P-gp) and cytochrome P450
(CYP)3A4. We determined the pharmacokinetic parameters of nifedipine and dehydronifedipine after
oral and intravenous administration of nifedipine to rats in the presence or absence of gliclazide (1.0
and 4.0 mg/kg). Gliclazide inhibited CYP3A4 enzyme activity in a concentration-dependent manner

투고일자 2016.2.2; 심사완료일자 2016.2.17; 게재확정일자 2016.2.24

�교신저자 최인 Tel:062-220-3291 E-mail:csh1987045@chosun.ac.kr

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 JKSHP, VOL.33, NO.1 (2016)

with a 50% inhibitory concentration (IC50) of 12.5 μ

M. The areas under the plasma concentration-time
curve (AUC0-∞) and the peak concentration (Cmax) of nifedipine were significantly (4.0 mg/kg, P<0.05)
increased by 39.0% and 34.8%, respectively, in the presence of gliclazide, as compare to those of con-
trol. In addition, the total body clearance (CL/F) was significantly (4.0 mg/kg, P<0.05) decreased by
the treatment with gliclazide (47.9%). Consequently, the absolute bioavailability (AB) of nifedipine in
the presence of gliclazide (4.0 mg/kg) was significantly (P<0.05) higher (39.2%) than that of the con-
trol group. The metabolite-parent AUC ratio (MR) of nifedipine was significantly decreased by treat-
ment with gliclazide (19.8%). The AUC0-∞ of intravenous nifedipine was significantly (4.0 mg/kg,
P<0.05) higher than that of the control group (18.1%), which suggested that gliclazide inhibited the
metabolism of nifedipine.
The increased bioavailability of nifedipine in the presence of gliclazide may be due to an inhibition
of the CYP3A4-mediated metabolism in the small intestine and/or in the liver and gliclazide-mediat-
ed reduction of CL/F of nifedipine.

[Key words] Nifedipine, Dehydronifedipine, Gliclazide, Pharmacokinetics, Bioavailability

INTRODUCTION gen delivery to the myocardial tissue, and

Nifedipine is a calcium channel-blocking agent
that is widely used for the treatment of essential
hypertension, coronary artery spasm and angina
pectoris. Nifedipine inhibits the influx of extra-
cellular calcium through myocardial and vascu-
lar membrane pores by physically plugging the
channel, which results in decreased intracellular
calcium levels, inhibition of the contractile
processes of smooth muscle cells, dilation of the
coronary and systemic arteries, increased oxy-
decreased total peripheral resistance, systemic
blood pressure and after load.
In humans, nifedipine is predominantly
metabolized by CYP3A4 to its primary pyridine
metabolite, dehydronifedipine.1) CYP enzymes
are responsible for the oxidative metabolism of
many xenobiotics and play a major role in the
phase I metabolism of many drugs.2) CYP3A4 is
the most abundant CYP enzyme (30-40%) in
adult liver and metabolizes more than 50% of
the clinically used drugs including nifedipine,

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 임태환 : 니페디핀과 그리크라지드와의 약동학적 상호작용
cyclosporine, midazolam and erythromycin.3)
Some studies indicate that nifedipine is a sub-
strate of CYP3A4 in human.4) P-gp is an adeno-
sine-50-triphosphate (ATP) dependent efflux
drug transporter that is constitutively expressed
in normal tissues that includes gastrointestinal
epithelium, canalicular membrane of the liver
and capillary endothelial cells in the central
nervous system.5) Because of such tissue local-
ized and its broad substrate specificity, P-gp
appears to play a key role in absorption, distri-
6)
bution and elimination of many drugs. It is
generally known that the substrate and/or
inhibitors of CYP3A4 and P-gp overlap with
each other. Dorababu et al.7) reported that
nifedipine belonged to a group of P-gp sub-
strate. Since P-gp is co-localized with CYP3A4
in the small intestine, P-gp and CYP3A4 may
act synergistically to promote presystemic drug
metabolism, which may result in the limited
absorption of drugs.
Gliclazide, 3-(7-azabicyclo [3.3.0] oct-7-yl)-1-
(4-methylphenyl) sulfonylurea is a second-gen-
eration, widely used for the treatment of non-
insulin-dependent diabetes mellitus.8) Oral
hypoglycaemic agents remain the cornerstone of
the treatment of Type 2 diabetes in patients not
responsive to diet, exercise and weight reduc-
tion. Of the various oral hypoglycaemic agents
available, sulphonylureas and biguanides are
considered the first-line treatment. Amongst
the sulphonylureas, gliclazide is widely used.
Considerable interindividual variability in meta-
bolic clearance is a feature of the
sulphonylureas9) and differences in elimination
are believed to contribute to therapeutic out-
come and the occurrence of adverse effects.9)
Despite the widespread use of gliclazide, factors
that contribute to pharmacokinetic variability
have received less attention than for other
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sulphonylureas.9) In vitro, the effects of gli-
clazide on the CYP3A4-inhibition and P-gp-
inhibition activities have not been reported.
Thus, we attempted to evaluate the CYP3A4
activity of gliclazide, and furthermore, to evalu-
ate the P-gp activity using rhodamine-123
retention assay in P-gp-overexpressed MCF-
7/ADR cells.
Although a combination of gliclazide and
nifedipine have been clinically prescribed for the
prevention or treatment of cardiovascular dis-
eases with diabetes, the pharmacokinetic inter-
action between gliclazide and nifedipine has not
been reported in vivo thus far. Therefore, in this
study we aimed to investigate the possible
effects of gliclazide on the activities of CYP3A4
and P-gp and bioavailability & the pharmacoki-
netics of nifedipine and its active metabolite,
dehydronifedipine, after oral and intravenous
administration of nifedipine with gliclazide in
rats.
METHODS
Materials
Nifedipine, dehydronifedipine, gliclazide and
amlodipine [internal standard for the high-per-
formance liquid chromatographic (HPLC) analy-
sis of nifedipine] were purchased from the
Sigma-Aldrich Co. (St. Louis, MO, USA).
Methanol, isooctane, methyl-tert-butyl ether
(MTBE), analytical grade acetic acid and triethy-
lamine (TEA) were products from Merck Co.
(Darmstadt, Germany). Rhodamine was from
Calbiochem (USA), the CYP inhibition assay kit
was from GENTEST (Woburn, MA, US). Other
chemicals were of reagent or HPLC grade.
Apparatus used in this study included an HPLC
system equipped with a Waters 1515 isocratic
 JKSHP, VOL.33, NO.1 (2016)
HPLC Pump, a Waters 717 plus auto sampler
TM
and a Waters 2487 scanning UV detector
(Waters Co., Milford, MA, USA), an HPLC col-
umn temperature controller (Phenomenex Inc.,
CA, USA), a Bransonic� Ultrasonic Cleaner
(Branson Ultrasonic Co., Danbury, CT, USA), a
vortex-mixer (Scientific Industries Co., NY,
USA), and a high-speed microcentrifuge
(Hitachi Co., Tokyo, Japan).
Animal studies
All animal study protocols were approved by
the Animal Care Committee of Chosun
University (Gwangju, Republic of Korea). Male
Sprague-Dawley rats (270-300 g) were pur-
chased from Dae Han Laboratory Animal
Research Co. (Eumsung, Republic of Korea), and
they were given free access to a normal stan-
dard chow diet (No. 322-7-1; Superfeed Co.,
Wonju, Republic of Korea) and tap water.
Throughout the experiments, the animals were
housed, four or five per cage, in laminar flow
cages maintained at 22 ± 2℃, 50-60% relative
humidity, under a 12 h light-dark cycle. The
rats were acclimated under these conditions for
at least 1 week. Each rat was fasted for at least
24 h before the experiment. The left femoral
artery (for blood sampling) and left femoral vein
(for iv administration of the drug) were cannu-
lated using a polyethylene tube (SP45; i.d., 0.58
mm, o.d., 0.96 mm; Natsume Seisakusho
Company, Tokyo, Japan) while each rat was
under light ether anesthesia.
Intravenous and oral administration of nifedipine
The rats were divided into six groups (n=6,
each): oral groups [10 mg/kg of nifedipine dis-
solved in distilled water (1.0 mL/kg)] without
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(control) or with 1.0 and 4.0 mg/kg of gliclazide
(mixed in distilled water; total oral volume of 1.0
mL/kg) and intravenous groups (2.5 mg/kg of
nifedipine; the same solution used: 0.9% NaCl-
injectable solution; total injection volume of 1.0
mL/kg) without (control) or with 1.0 and 4.0
mg/kg of gliclazide. A feeding tube was used to
administer nifedipine and gliclazide intragastri-
cally. Gliclazide was administered 30 min prior
to oral administration of nifedipine. A blood
sample (0.3-mL aliquot) was collected from the
femoral artery into heparinized tubes at 0.017
(at the end of infusion), 0.1, 0.25, 0.5, 1, 2, 4, 8,
12 and 24 h for the intravenous study, and 0.25,
0.5, 0.75, 1, 2, 4, 8, 12 and 24 h for the oral
study. Whole blood (approximately 1.2 mL) col-
lected from untreated rats was infused via the
femoral artery at 0.75, 4 and 8 h, respectively,
to replace blood loss caused by blood sampling.
The blood samples were centrifuged (13,000
rpm, 3 min), and a 150-μ
L aliquot of plasma
samples was stored in the deep freezer at -40℃
until the HPLC analysis.
HPLC assay
The plasma concentrations of nifedipine were
determined using an HPLC assay with a modifi-
cation to the method reported by Grundy et al.10)
Briefly, 50-μ
L of amlodipine (3 μ
g/mL), as the
internal standard and 50-μ
L of 1.0 M sodium
hydroxide were added to 0.15-mL of the plasma
sample. It was then mixed for 3 s and 1-mL
MTBE-isooctane (75:25, v/v) was added. The
resultant mixture was vortex-mixed for 1 min
and centrifuged at 3,000 rpm for 5 min. The
organic layer (0.8 mL) was transferred into a
clean test tube and evaporated under a gentle
stream of nitrogen gas (no heat applied). The
dried extract was reconstituted with 200 μ
L of
 임태환 : 니페디핀과 그리크라지드와의 약동학적 상호작용
the mobile phase vortex-mixed for 1 min and
aliquots of 160 μ
L were transferred to a clean
autosampler vial. A 70-μ
L aliquot of the super-
natant was injected into the HPLC system. The
UV detector wavelength was set to 350 nm; and
the column, a Nova-pack C8 (100 mm×8 mm
i.d., 4 μ
m; Waters Co., Milford, MA, USA), was
used at room temperature. A mixture of
methanol:water (62:38, v/v, pH 4.5, adjusted
with acetic acid, 320 μ
L of TEA/1,000 mL mix-
ture) was used as the mobile phase at a flow
rate of 1.0 mL/min. The retention times were:
internal standard at 16.8 min, nifedipine at 8.2
min, and dehydronifedipine at 6.5 min. The
detection limits of nifedipine and dehy-
dronifedipine in rat plasma were all 5 ng/mL.
The coefficients of variation for nifedipine and
dehydronifedipine were all below 5.0%.
CYP3A4 inhibition assay
The assay of inhibitory activities on the human
CYP3A4 enzyme activity was performed in a
multiwell plate using CYP inhibition assay kit
(GENTEST, Woburn, MA) as described previous-
11)
ly. Briefly, human CYP enzyme was obtained
from baculovirus-infected insect cells. CYP
substrate (7-BFC for CYP3A4) was incubated
with or without test compounds in the enzyme
/substrate buffer with 1 pmol of P450 enzyme
and an NADPH-generating system (1.3 mM
NADP, 3.54 mM glucose 6-phosphate, 0.4 U/mL
glucose 6-phosphate dehydrogenase and 3.3
mM MgCl2) in potassium phosphate buffer (pH
7.4). Reactions were terminated by adding stop
solution after 45 min incubation. Metabolite
concentrations were measured using spectroflu-
orometer (Molecular Device, Sunnyvale, CA) at an
excitation wavelength of 409 nm and an emis-
sion wavelength of 530 nm. Positive control (1 μ
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M ketoconazole for CYP3A4) was run on the
same plate and showed 99% inhibition. All
experiments were done in duplicate, and the
results were expressed as the percent of inhibi-
tion.
Rhodamine-123 retention assay
The procedure used for the Rho-123 retention
assay was similar to that reported previously.12)
MCF-7/ADR cells were seeded in 24-well plates.
At 80% confluence, the cells were incubated in
FBS-free DMEM for 18 h. The culture medium
was changed to Hanks’balanced salt solution
and the cells were incubated at 37℃ for 30 min.
After incubation of the cells with 20 μ
M rho-
damine-123 in the presence or absence of gli-
clazide (10, 30 and 100 μ
M) and verapamil (posi-
tive control, 100 μ
M) for 90 min, the medium
was completely removed. The cells were then
washed three times with ice-cold phosphate
buffer (pH 7.0) and lysed in EBC lysis buffer.
Rhodamine-123 fluorescence in the cell lysates
was measured using excitation and emission
wavelengths of 480 and 540 nm, respectively.
Fluorescence values were normalized to the total
protein content of each sample and were pre-
sented as the ratio to control.
Pharmacokinetic analysis
The plasma concentration data were analyzed
by the non-compartmental method using
Thermo Kinetica Software Version 5.0 (Thermo
Fisher Scientific Inc., Miami, OK, USA). The
parameter values were obtained by fitting to the
pharmacokinetic model using the simplex algo-
rithm. The area under the plasma concentra-
tion-time curve (AUC0-∞) was calculated by a
trapezoidal rule. The peak concentration (Cmax)
 JKSHP, VOL.33, NO.1 (2016)
of nifedipine in plasma and time to reach peak
concentration (Tmax) were obtained by visual
inspection of the data from the concentration-
time curve. The terminal half-life (t1/2) was cal-
culated by 0.693/Kel. Total body clearance (CL/F)
was calculated using the equation dose/AUC.
The absolute bioavailability (AB) was calculated
using the equation AUCoral/AUCi.v.×dosei.v./
doseoral, and the relative bioavailability (RB) of
nifedipine were calculated using the equation
AUCnifedipine with gliclazide/ AUCcontrol. The metabo-
lite-parent AUC ratio (MR) was calculated using
the equation AUCdehy-dronifedipine/AUCnifedipine.
Statistical analysis
All the means were presented with their stan-
dard deviation. The pharmacokinetic parameters
were compared with a one-way ANOVA, fol-
lowed by a posteriori testing with the use of the
Dunnett correction. A P value < 0.05 was con-
sidered statistically significant.
RESULTS
Log concentration of ketoconazole(μM)
Fig. 1 Inhibitory effect of ketoconazole and gliclazide on CYP3A4 activity.
The results were expressed as the percent of inhibition.
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Inhibitory Effect of Gliclazide on CYP3A4 Activity
The inhibitory effect of gliclazide on CYP3A4
activity is shown in Fig. 1. Gliclazide inhibited
CYP3A4 activity in a concentration-dependent
manner. Gliclazide inhibited CYP3A4 activity
with an IC50 value of 12.5 μ
M.
Rhodamine-123 Retention Assay
Accumulation of rhodamine-123, a P-glyco-
protein substrate, was decreased in MCF-7/ADR
cells overexpressing P-glycoprotein compared to
that in MCF-7 cells lacking P-glycoprotein, as
shown in Fig. 2. The concurrent use of gliclazide
did not enhance the cellular uptake of rho-
damine-123. This result suggests that gliclazide
did not inhibit the P-gp activity.
Effect of Gliclazide on the Pharmacokinetics of
oral Nifedipine
The mean plasma concentration-time profiles
of nifedipine without or with of gliclazide (1.0
Log concentration of gliclazide(μM)
 임태환 : 니페디핀과 그리크라지드와의 약동학적 상호작용

Fig. 2 Effects of gliclazide on the cellular accumulation of rhodamine-123 in MCF-7 and MCF-7/ADR cells.
Data represents mean ± SD (n=6).

Fig. 3 Mean arterial plasma concentration-time profiles of nifedipine after oral (10 mg/kg) administration
of nifedipine with gliclazide to rats (mean ± SD, n=6).
● - Control (nifedipine alone, 10 mg/kg)
○ - with 1.0 mg/kg gliclazide
▼ - with 4.0 mg/kg gliclazide
* - P<0.05

and 4.0 mg/kg) are shown in Fig. 3. The phar-
macokinetic parameters of nifedipine are sum-
marized in Table 1. Gliclazide (4.0 mg/kg) signif-
icantly (P<0.05) increased the area under the
plasma concentration-time curve from time zero
to time infinity (AUC0-∞) of nifedipine by 39.0%,
and peak concentration (Cmax) of nifedipine by
34.8%. The total body clearance (CL/F) was sig-
nificantly decreased (4.0 mg/kg, P<0.05) by gli-
clazide (47.9%). Accordingly, the absolute
bioavailability (AB) values of nifedipine in the
presence of gliclazide (4.0 mg/kg) were signifi-

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 JKSHP, VOL.33, NO.1 (2016)

Table 1. Mean (± SD, n=6) pharmacokinetic parameters of nifedipine after oral (10 mg/kg) administration
of nifedipine without or with gliclazide in rats

Nifedipine + gliclazide
Parameter Control
1.0 mg∙kg-1 4.0 mg∙kg-1
AUC0-∞ (ng∙ml-1∙h) 5,893 ± 1,063 6,541 ± 1,252 8,191 ± 1,521*
-1
Cmax (ng∙ml ) 1,130 ± 223 1,192 ± 232 1,522 ± 308*

Tmax (h) 0.75 ± 0.10 0.75 ± 0.10 0.75 ± 0.12

t1/2 (h) 9.3 ± 1.8 10.0 ± 2.0 10.1 ± 2.3

-1
CL/F (ml∙min ) 1.81 ± 0.31 1.40 ± 0.28 0.94 ± 0.18*

AB (%) 15.8 ± 2.9 17.8 ± 3.5 21.8 ± 3.7*

RB (%) 100 111 139

* P<0.05, statistically significant different from the control
Abbreviations: AUC0-∞: area under the plasma concentration-time curve from 0 h to infinity; Cmax: peak plasma concentration; Tmax: time to reach peak
plasma concentration; t1/2: terminal half-life; CL/F: total body clearance; AB: absolute bioavailability; RB: relative bioavailability.

Fig. 4 Mean arterial plasma concentration-time profiles of dehydronifedipine after oral administration
of nifedipine (10 mg/kg) with gliclazide to rats (mean ± SD, n=6).
● - Control (nifedipine alone, 10 mg/kg)
○ - with 1.0 mg/kg gliclazide
▼ - with 4.0 mg/kg gliclazide

cantly (P<0.05) higher (39.2%) than that of the presence of gliclazide.

control group. Gliclazide increased the relative
bioavailability (RB) of nifedipine by 1.11- to Effect of Gliclazide on the Pharmacokinetics of
1.39-fold. There were no significant differences Dehydronifedipine
in the time to reach peak plasma concentration
(Tmax), terminal half-life (t1/2) of nifedipine in the The plasma concentration-time profiles of

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 임태환 : 니페디핀과 그리크라지드와의 약동학적 상호작용

Table 2. Mean (± SD, n=6) pharmacokinetic parameters of dehydronifedipine following an oral adminis-
tration of nifedipine (10 mg/kg) without or with gliclazide in rats

Nifedipine + gliclazide
Parameter Control
1.0 mg∙kg-1 4.0 mg∙kg-1
AUC0-∞ (ng∙ml-1∙h) 2,142 ± 373 2,314 ± 421 2,399 ± 431
-1
Cmax (ng∙ml ) 108 ± 19.1 112 ± 21.0 115 ± 21.2

Tmax (h) 1.7 ± 0.5 1.8 ± 0.5 1.8 ± 0.6

t1/2 (h) 14.5 ± 2.5 15.4 ± 2.6 16.0 ± 2.7

RB (%) 100 108 112

MR 36.4 ± 3.6 35.3 ± 3.4 29.2 ± 3.1*

* P<0.05, statistically significant different from the control,
Abbreviations: AUC0-∞: area under the plasma concentration-time curve from 0 h to infinity; Cmax: peak plasma concentration; Tmax: time to reach peak
plasma concentration; t1/2: terminal half-life; RB: relative bioavailability; MR: metabolite-parent AUC ratio.

Fig. 5 Mean arterial plasma concentration-time profiles of nifedipine after intravenous (2.5 mg/kg)
administration of nifedipine with gliclazide to rats (mean ± SD, n=6).
● - Control (nifedipine alone, 2.5 mg/kg)
○ - with 1.0 mg/kg gliclazide,
▼ - with 4.0 mg/kg gliclazide, *, P<0.05.

dehydronifedipine are shown in Figure 4. The that gliclazide inhibited metabolism of nifedip-
pharmacokinetic parameters of dehydronifedip- ine.
ine are summarized in Table 2. The AUC0-∞ of
dehydronifedipine was not significant greater Effect of Gliclazide on the Pharmacokinetics of
than that of the control group by gliclazide. The Intravenous Nifedipine
MR ratio of nifedipine was significantly
decreased (19.8%) by gliclazide, which suggested Mean plasma concentration-time profiles of

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Table 3. Mean (± SD, n=6) pharmacokinetic parameters of nifedipine after intravenous (2.5 mg/kg)
administration of nifedipine without or with gliclazide in rats
Parameter Control
AUC0-∞ (ng∙ml-1∙h) 9,299 ± 1,401
-1
CLt (ml∙min ) 4.5 ± 0.5
t1/2 (h) 8.3 ± 1.5
RB (%) 100
* P<0.05, statistically significant different from the control,
Abbreviations: AUC0-∞: area under the plasma concentration-time curve from 0 h to infinity; CLt: total body clearance; t1/2: terminal half-life; RB: relative
bioavailability
nifedipine following an intravenous administra-
tion of nifedipine (2.5 mg/kg) to rats without or
with of gliclazide (1.0 and 4.0 mg/kg) are shown
in Fig. 5, while the corresponding pharmacoki-
netic parameters are shown in Table 3. The
AUC0-∞ of intravenous nifedipine was signifi-
cantly higher than that of the control group
(18.1%), which suggested that gliclazide inhibited
metabolism of nifedipine.
Accordingly, the increased of nifedipine in the
presence of gliclazide may be attributed to inhi-
bition of the CYP3A4-mediated metabolism of
nifedipine in the small intestine and/or in the
liver by gliclazide.
DISCUSSION
The study of mechanisms of drug interactions
is of much value in selecting the drug combina-
13)
tions to provide rational therapy.
interaction studies assume much importance
especially for drugs that have narrow margin of
safety and where the drugs are used for pro-
longed period of time. Diabetes mellitus is one
such metabolic disorder that needs treatment for
prolonged periods. Chronic diabetes leads to
JKSHP, VOL.33, NO.1 (2016)
Nifedipine + gliclazide
1.0 mg∙kg-1 4.0 mg∙kg-1
9,955 ± 1,508 10,979 ± 1,551*
4.2 ± 0.4 4.0 ± 0.4
8.6 ± 1.6 8.8 ± 1.9
107 118
several complications, which includes cardiovas-
cular, renal, retinal and fungal infections etc.,
out of which cardiovascular complications are
more prevalent.13) Angina pectoris one such
complication which is commonly seen in many
chronic diabetics.14)-16) According to EUROPA
study, the incidence of angina is more in people
with type II diabetes and 12% of people from a
normal population with angina or heart disease
also had diabetes.17) Nifedipine is widely used for
the treatment of essential hypertension, coro-
nary artery spasm, and angina pectoris.
Gliclazide is a second-generation sulfonylurea,
widely used for the treatment of non-insulin-
dependent diabetes mellitus.8) In clinic, gliclazide
and nifedipine could be prescribed for the pre-
vention or treatment of cardiovascular diseases
as complications of diabetes.
In Fig. 1, the inhibitory effect of gliclazide on
The drug CYP3A4 activity is shown and gliclazide inhibit-
ed CYP3A4 activity with an IC50 value of 12.5 μ
M. In Figure 2, The concurrent use of gliclazide
did not enhance the cellular uptake of rho-
damine-123. This result suggested that gli-
clazide did not inhibit P-gp activity. Some in-
vitro and in-vivo studies have indicated that
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 임태환 : 니페디핀과 그리크라지드와의 약동학적 상호작용
nifedipine is metabolized to dehydronifedipine
5)
mainly by CYP3A4 enzymes. As CYP3A4
expressed in rat is corresponding to the fuction
18)
of CYP3A4 in human. This study evaluated the
influence of gliclazide on the pharmacokinetics
of nifedipine in rats in order to assess the
potential drug interactions between gliclazide
and nifedipine. Considering that nifedipine is a
substrate of both CYP3A4 enzymes, gliclazide
may significantly impact the pharmacokinetics
and bioavailability of nifedipine.
As shown in Table 1, the coadministration of
gliclazide (4.0 mg/kg) significantly altered the
pharmacokinetic profiles of nifedipine compared
with the administration of nifedipine alone.
Consequently, the relative bioavailability of
nifedipine increased by 1.11- to 1.39-fold than
those of the control group. Our results were
consistent with those reported previously, which
showed that oral diallyl trisulfide (major
organosulfur compounds derived from garlic)
significantly increased the bioavailability of
nifedipine by inhibition of CYP3A4 in rats.19) Our
results are also consistent with those reported
that showed that ketoconazole, Coenzyme Q10
and licochalcone A significantly increased the
AUC0-∞ and Cmax of nifedipine.20)-22) After intra-
venous administration of nifedipine with gli-
clazide, the AUC0-∞ of nifedipine was signifi-
cantly increased by gliclazide (Table 3). The MR
ratios of nifedipine was significantly decreased
(19.8%) by gliclazide, which suggested that gli-
clazide inhibited metabolism of nifedipine (Table
2). Our results are also consistent with those
reported that showed that licochalcone A signif-
icantly decreased the MR ratios of nifedipine.22)
In conclusion, the increased bioavailability of
nifedipine in the presence of gliclazide could be
attributed to the inhibition of CYP3A4-mediated
metabolism in the small intestine and/or in the
- 59 -
liver and/or to the reduction of CL/F of nifedip-
ine by gliclazide. Concomitant use of nifedipine
with gliclazide may require close monitoring for
potential drug interactions. Further studies
should be performed to determine drug interac-
tions associated with in human.
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