Cyp3 a4 nimoidipine

Pharmacological Reports Copyright © 2011
2011, 63, 1066–1073 by Institute of Pharmacology
ISSN 1734-1140 Polish Academy of Sciences

Short communication

Effects of the antioxidant baicalein on
the pharmacokinetics of nimodipine in rats:
a possible role of P-glycoprotein and CYP3A4
inhibition by baicalein
Young-Ah Cho1, Jun-Shik Choi2 Jin-Pil Burm3
1
School of Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 660-701,
Republic of Korea

2
College of Pharmacy, Chosun University, Gwangju 501-759, Republic of Korea

3
College of Nursing, Chosun Nursing College, Gwangju 501-825, Republic of Korea

Correspondence: Jin-Pil Burm, e-mail: jpburm@cnc.ac.kr

Abstract:
The reduced bioavailability of nimodipine after oral administration might not only be due to the metabolizing enzyme cytochrome
P450 3A4(CYP3A4) but also to the P-glycoprotein efflux transporter in the small intestine. The aim of this study was to investigate
the effects of baicalein on the pharmacokinetics of nimodipine in rats. The effect of baicalein on P-glycoprotein and CYP3A4 activ-
ity was evaluated. A single dose of nimodipine was administered intravenously (3 mg/kg) and orally (12 mg/kg) to rats in the pres-
ence and absence of baicalein (0.4, 2 and 8 mg/kg). Baicalein inhibited CYP3A4 enzyme activity in a concentration-dependent
manner, with a 50% inhibition concentration (IC50) of 9.2 µM. In addition, baicalein significantly enhanced the cellular accumula-
tion of rhodamine-123 in MCF-7/ADR cells overexpressing P-glycoprotein. Baicalein significantly altered the pharmacokinetics of
orally administered nimodipine. Compared to the oral control group given nimodipine alone, the area under the plasma
concentration-time curve (AUC0–¥) and the peak plasma concentration (Cmax) of nimodipine significantly increased (p < 0.05 for
2 mg/kg; p < 0.01 for 8 mg/kg). Consequently, the absolute bioavailability of nimodipine in the presence of baicalein (2 and 8 mg/kg)
was 31.0–35.3%, which was significantly enhanced (p < 0.05 for 2 mg/kg; p < 0.01 for 8 mg/kg) compared to the oral control group
(22.3%). Moreover, the relative bioavailability of nimodipine was 1.39- to 1.58-fold greater than that of the control group. The phar-
macokinetics of intravenous nimodipine were not affected by baicalein in contrast to those of oral nimodipine. Baicalein signifi-
cantly enhanced the oral bioavailability of nimodipine, which may be mainly due to inhibition of the CYP3A4-mediated metabolism
of nimodipine in the small intestine and/or in the liver and the inhibition of the P-glycoprotein efflux pump in the small intestine by
baicalein. The increase in oral bioavailability of nimodipine in the presence of baicalein should be taken into consideration as a po-
tential drug interaction between nimodipine and baicalein.

Key words:
nimodipine, baicalein, pharmacokinetics, bioavailability, P-glycoprotein, CYP3A4

1066 Pharmacological Reports, 2011, 63, 1066–1073

Effects of baicalein on nimodipine pharmacokinetics
Young-Ah Cho et al.

stitute up to 20% of the dry weight of S. radix [25,
Introduction
32]. After digestion, the glucuronides are readily hy-
drolyzed by intestinal bacteria [18]. Baicalein and re-
lated flavonoids are the major components responsible
Nimodipine is a dihydropyridine calcium channel
for the pharmacological effects of S. radix [16, 20].
blocker that has been shown to selectively dilate cere-
Baicalein inhibits the testosterone 6b-hydroxyl-
bral arteries and increase cerebral blood flow in ani-
ation activity of CYP3A4 and can also inhibit P-gly-
mals and humans [12]. Its major therapeutic indica-
coprotein in the multidrug resistant (TB/MDR) cell
tion is for the prevention and treatment of delayed
system [15], but the inhibitory effect of baicalein on
ischemic neurological disorders that often occur in
CYP3A4 and P-glycoprotein is partially ambiguous.
patients with subarachnoid hemorrhages [7, 27]. Ni-
Thus, we reevaluated CYP3A4 and P-glycoprotein
modipine is rapidly absorbed after oral administration activity using the rhodamine-123 retention assay in
and is widely distributed throughout the body. Orally the adriamycin-resistant human breast cancer cell line
administered nimodipine undergoes an extensive (MCF-7/ADR) overexpressing P-glycoprotein. The
first-pass hepatic metabolism from the portal circula- effect of baicalein was similar to that of quercetin [13]
tion, resulting in a low systemic bioavailability [19, and morin [2]. There are a few interactions between
30]. Usually only the parent compound is active and flavonoids and nimodipine [2]. However, little infor-
most of the metabolic steps involve reactions cata- mation is available regarding the in vivo effects of
lyzed by cytochrome P450 (CYP) enzymes. CYP en- these flavonoids on the pharmacokinetics of nimodip-
zymes have been shown to catalyze pyridine forma- ine. Baicalein and nimodipine could be prescribed as
tion, methyl hydroxylation, and various modes of a combination therapy [21]. Therefore, the aim of this
side-chain oxidation [23, 26]. study was to examine the effects of the antioxidant
The reduced bioavailability of nimodipine after oral ad- baicalein on CYP3A4 and P-glycoprotein activity on
ministration orally might not only be due to the metaboliz- the pharmacokinetics of nimodipine after oral admini-
ing enzyme CYP3A4 but also to the P-glycoprotein ef- stration of baicalein in rats.
flux transporter in the small intestine. Saeki et al. [24]
reported that nimodipine is a substrate for P-glyco-
protein-driven efflux, and Wacher et al. [33] reported
that nimodipine is a substrate for both CYP3A4 and
P-glycoprotein. P-glycoprotein is found in the secre- Materials and Methods
tory epithelial tissues, including the brush border of
the renal proximal tubules, the canalicular membranes Materials
in the liver and the apical membranes lining the gut.
In the small intestine, P-glycoprotein and CYP3A4 Nimodipine, nitrendipine (internal standard) and bai-
co-localize at the apical membrane of cells [9]. P-gly- calein were purchased from Sigma Chemical Co. (St.
coprotein and CYP3A4 may act synergistically during Louis, MO, USA). Ethyl acetate and methanol were
presystemic drug metabolism to cause the substrate of purchased from Merck Co. (Darmstadt, Germany). All
P-glycoprotein to move between the lumen and other chemicals were reagent grade and were used
epithelial cells, leading to prolonged exposure to without further purification. The apparatuses used in-
CYP3A4 and therby a reduced absorption of the drug cluded HPLC (Model LC-10A, Shimadzu Co., Kyoto,
[8, 10, 33, 34]. Japan), a syringe pump (Model341B, Sage Co., Kyoto,
Flavonoids are phytochemicals produced in high Japan), a vortex mixer (Scientific Industries, Seoul,
quantities by various plants [6]. These compounds ex- Korea) and a centrifuge (Abbot Co., TM, USA).
hibit a wide range of beneficial biological activities
including antioxidative, radical scavenging, antiathe- Animal experiments
rosclerotic, antitumor and antiviral effects [21]. Fla-
vonoids also modulate the CYP3A subfamily and/or Male Sprague-Dawley rats weighing 270–300 g were
P-glycoprotein [1, 5, 14]. Baicalein is the major fla- purchased from the Dae Han Laboratory Animal Re-
vonoid in Scutellariae radix and is mainly present in search Co. (Choongbuk, Korea) and were given ac-
its glucuronide form. Baicalein glucuronides can con- cess to a commercial rat chow diet (No. 322-7-1, Su-

Pharmacological Reports, 2011, 63, 1066–1073 1067

perfeed Co., Gangwon, Korea) and tap water. The ani- The HPLC system consisted of two solvent deliv-
mals were housed two per cage and maintained at ery pumps (Model LC-10AD, Shimadzu Co., Japan),
22 ± 2°C and 50–60% relative humidity under a 12:12 a UV detector (Model SPD-10A), a system controller
h light-dark cycle. The experiments were initiated af- (Model SCL-10A), a degasser (Model DGU-12A) and
ter acclimation under these conditions for at least an auto injector (SIL-10AD). The UV detector was set
1-week. The Animal Care Committee of Chosun Uni- at a wavelength of 310 nm. The stationary phase was
versity (Gwangju, Korea) approved the design and a Hypersil ODS column (5 µm, 4.6 × 150 mm). The
conduction of this study. The rats fasted for at least mobile phase consisted of methanol and water (65:35,
24 h prior to the experiments, and each animal was v/v). The mobile phase was filtered by passage
anesthetized lightly with diethyl ether. The left femo- through a 0.45-µm pore size membrane filter. The re-
ral artery and vein were cannulated using polyethyl- tention times at a flow rate of 1.0 ml/min were as fol-
ene tubing (SP45, i.d. 0.58 mm, o.d. 0.96 mm; Nat- lows: internal standard, 7.6 min; nimodipine, 9.1 min.
sume Seisakusho Co. LTD., Tokyo, Japan) for blood Linear regression analysis using a least-square fit was
sampling and intravenous injection, respectively. performed. The calibration curve was obtained from
the standard samples at 10, 20, 50, 100, 500, and
1,000 ng/ml. The regression equation obtained was
Drug administration
y = 206.0x + 18.1 (r = 0.999). The limit of detection
(LOD) of nimodipine in rat’s plasma was 3.3 ng/ml
The rats were divided into four groups (n = 6): an oral
(S/N ratio = 3). The coefficients of variation for nimo-
control group (12 mg/kg of nimodipine dissolved in
dipine were below 12.5%.
distilled water, 3.0 ml/kg) with or without 0.4, 2 and
8 mg/kg of baicalein (mixed in distilled water, 3.0 ml/
CYP3A4 inhibition assay
kg), and an intravenous (iv) group (3 mg/kg of nimo-
dipine, dissolved in 0.9% NaCl solution, 1.5 ml/kg).
To assay the inhibition of human CYP3A4 enzyme
Oral nimodipine was administered intragastrically us-
activity, a CYP inhibition assay kit (GENTEST,
ing a feeding tube, and baicalein was administered in
Woburn, MA) was used in a multiwell plate as
the same manner 30 min prior to the oral administra-
described previously [3]. Briefly, human CYP was
tion of nimodipine. Nimodipine for iv administration
obtained from baculovirus-infected insect cells. The
was injected through the femoral vein within 0.5 min.
CYP substrate 7-benzyloxy-4-trifluoromethylcoumarin
A 0.4 ml of blood was collected into heparinized
(BFC) was incubated with or without test compounds
tubes from the femoral artery at 0 (to serve as con-
in the buffer containing enzyme and substrate with
trol), 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24 and 36 h after ni-
1 pmol of P450 enzyme and an NADPH-generating sys-
modipine administration. The blood samples were
tem (1.3 mM NADP, 3.54 mM glucose 6-phosphate,
centrifuged at 16,800 × g for 5 min, and the plasma
0.4 U/ml glucose 6-phosphate dehydrogenase and
samples were stored at –40°C until HPLC analysis.
3.3 mM MgCl2) in a potassium phosphate buffer (pH
7.4). Reactions were terminated by adding stop solu-
HPLC assay tion after a 45-min incubation. Metabolite concentra-
tions were measured by spectrofluorometry (Molecular
The plasma nimodipine concentration was determined Device, Sunnyvale, CA) at an excitation wavelength of
by an HPLC assay using a modification of the method 409 nm and an emission wavelength of 530 nm. The
reported by Qian et al. [22]. Briefly, 50 µl of nitren- positive control (1 µM ketoconazole for CYP3A4) was
dipine (1 µg/ml) as the internal standard and 50 µl of run on the same plate and produced 99% inhibition. All
ethyl acetate were added to 0.2 ml of the plasma sam- experiments were conducted in duplicate, and the re-
ples. The mixture was stirred for 10 min and centri- sults are expressed as the percent of inhibition.
fuged at 3,000 rpm for 10 min. Next, 5 ml of the or-
ganic layer was transferred to a clean test tube and Rhodamine-123 retention assay
evaporated at 40°C under a stream of nitrogen. The
residue was then dissolved in 300 µl of 65% metha- MCF-7/ADR cells were seeded in 24-well plates. At
nol, centrifuged at 3,000 rpm for 10 min, and 50 µl of 80% confluence, the cells were incubated in fetal bo-
the solution was injected into the HPLC system. vine serum (FBS)-free Dulbecco’s modified Eagle’s


Young-Ah Cho et al.

medium (DMEM) for 18 h. The culture medium was
Results
changed to Hanks’ balanced salt solution and the cells
were incubated at 37°C for 30 min. After incubation of
the cells with 20 µM rhodamine-123 in the presence or Inhibition of CYP3A4
absence of baicalein (1, 3 and 10 µM) for 90 min, the
The inhibitory effect of baicalein on CYP3A4 activity
medium was completely removed. The cells were
is shown in Figure 1. Baicalein inhibited CYP3A4 ac-
then washed three times with ice-cold phosphate
tivity in a concentration-dependent manner. Baicalein
buffer (pH 7.0) and lysed in EBC lysis buffer.
inhibited human CYP3A4 with a 50% inhibition con-
Rhodamine-123 fluorescence in the cell lysates was
centration (IC50) value of 9.2 µM.
measured using excitation and emission wavelengths
of 480 and 540 nm, respectively. Fluorescence values
Rhodamine-123 retention assay
were normalized to the total protein content of each
sample and are presented as the ratio to control. The accumulation of rhodamine-123, a P-glycoprotein
substrate, in MCF-7/ADR cells overexpressing P-gly-
coprotein was greater than that of MCF-7 cells lack-
Pharmacokinetic analysis
ing P-glycoprotein, as shown in Figure 2. The concur-
rent use of baicalein enhanced the cellular uptake of
The plasma concentration data were analyzed using rhodamine-123 in a concentration-dependent manner
a non-compartmental method from WinNonlin soft- ranging from 1 to 10 µM. This result suggests that
ware, version 4.1 (Pharsight Co., Mountain View, CA, baicalein significantly (p < 0.05 and p < 0.01) inhib-
USA). The elimination rate constant (Kel) was calcu- ited P-glycoprotein activity.
lated using the log-linear regression of nimodipine con-
centration data during the elimination phase, and the
terminal half-life (t1/2) was calculated by 0.693/Kel. The
peak concentration (Cmax) and time to reach the peak
concentration (Tmax) of nimodipine in the plasma were
obtained by a visual inspection of the data from the
concentration-time curve. The area under the plasma
concentration-time curve (AUC0–t) from time zero to
the time of the last-measured concentration (Clast) was
calculated using the linear trapezoidal rule. The AUC
zero to infinity (AUC0–¥) was obtained by adding
AUC0–t, and the extrapolated area was calculated by
Clast/Kel. The total body clearance for the iv route (CLt)
was calculated as D/AUC, where D is the dose of ni-
modipine. The absolute bioavailability (AB) of nimo-
dipine was calculated by AUCoral/AUCiv × Doseiv/
Doseoral × 100; the relative bioavailability (RB) was
calculated as (AUCcontrol/AUCwith baicalein) × 100.

Statistical analysis

Fig. 1. The inhibitory effect of baicalein on CYP3A4 activity. The CYP
All data are presented the mean with standard devia- substrate 7-BFC was incubated with or without test compounds in
the enzyme/substrate mixture. Reactions were terminated by adding
tion. The analysis of variance (ANOVA) with Schef- stop solution after a 45-min incubation. Metabolite concentrations
were measured by spectrofluorometry with excitation and emission
fe’s test was used to determine significant differences wavelengths of 409 and 530 nm, respectively. The positive control
between the control groups and co-administration or (1 µM ketoconazole for CYP3A4) was run on the same plate and pro-
duced 99% inhibition. All experiments were conducted in duplicate,
pretreatment groups. A p value < 0.05 was considered and the results are expressed as the percent of inhibition (IC50:
significant. 9.2 µM)


uptake

Fig. 2. Rhodamine-123 retention. MCF-7/ADR cells were incubated
in FBS-free DMEM for 18 h and then with 20 µM rhodamine-123 in the
presence or absence of baicalein (1, 3 and 10 µM) for 90 min.
Rhodamine-123 fluorescence in the cell lysates was measured using Fig. 3. Mean plasma concentration-time profiles of nimodipine after
excitation and emission wavelengths of 480 and 540 nm, respec- the oral co-administration of nimodipine (12 mg/kg) and baicalein to
tively. The values were divided by the total protein contents of each rats. (l) Nimodipine control, (o) with 0.4 mg/kg baicalein, (q) with
sample. Data are represented as the mean ± SD (n = 6). * p < 0.05, 2 mg/kg baicalein, (<) with 8 mg/kg baicalein. Bars represent the
** p < 0.01, significant difference compared to control MCF-7 cells standard deviation (n = 6)

ine. Compared to the control group given oral nimodip-
Effect of baicalein on the pharmacokinetics of
oral nimodipine ine alone, baicalein significantly (p < 0.05 for 2 mg/kg;
p < 0.01 for 8 mg/kg) increased the area under the
The mean arterial plasma concentration-time profiles plasma concentration-time curve (AUC0–¥) and the peak
of nimodipine following an oral administration of ni- plasma concentration (Cmax) of nimodipine. Baicalein
modipine (12 mg/kg) to rats in the presence or ab- also significantly (p < 0.05 for 2 mg/kg; p < 0.01 for
sence of baicalein (0.4, 2 and 8 mg/kg) are shown in 8 mg/kg) increased the absolute bioavailability (AB) of
Figure 3, and the corresponding pharmacokinetic pa- nimodipine by 31.0–35.5% compared to the oral control
rameters are shown in Table 1. Baicalein significantly group (22.3%), and the relative bioavailability (RB) of
altered the pharmacokinetic parameters of nimodip- nimodipine was increased by 1.39- to 1.58-fold.

Tab. 1. Mean pharmacokinetic parameters of nimodipine after the oral administration of nimodipine (12 mg/kg) to rats with baicalein (0.4, 2 and
8 mg/kg)

Parameter Control Nimodipine with baicalein

0.4 mg/kg 2 mg/kg 8 mg/kg

AUC0–¥ (ng¡ ´ h/ml) 509 ± 112 587 ± 126 706 ± 165* 805 ± 178**
Cmax (ng/ml) 91 ± 16 95 ± 22 113 ± 17* 123 ± 25*
Tmax (h) 0.25 0.25 0.25 0.25
T1/2 (h) 7.4 ± 1.6 7.8 ± 1.9 8.2 ± 2.1 8.4 ± 2.3
AB (%) 22.3 ± 4.7 25.7 ± 5.9 31.0 ± 6.6* 35.3 ± 7.8**
RB (%) 100 115 139 158

The mean ± SD (n = 6), * p < 0.05, ** p < 0.01, significant difference compared to control, AUC0–¥ – area under the plasma concentration- time
curve from 0 h to infinity; Cmax – peak plasma concentration; Tmax – time to reach Cmax; T1/2 – terminal half-life; AB – absolute bioavailability; RB –
relative bioavailability


Young-Ah Cho et al.

were not affected by the concurrent use of baicalein in
contrast to those of oral nimodipine. Accordingly, the
enhanced oral bioavailability in the presence of bai-
calein without a significant change in the pharmacoki-
netics of intravenous nimodipine may be mainly due
to the inhibition of CYP3A-mediated metabolism of
nimodipine in the small intestine and/or in the liver
and to the inhibition of the P-glycoprotein efflux
pump in the small intestine by baicalein, rather than
renal elimination of nimodipine.

Discussion
Fig. 4. Mean plasma concentration-time profiles of nimodipine after
iv administration of nimodipine (3 mg/kg) and baicalein to rats. (l) Ni-
Based on the broad overlap in substrate specificities
modipine control, (o) with 0.4 mg/kg baicalein, (q) with 2 mg/kg bai- and the co-localization in the small intestine, the pri-
calein, (<) with 8 mg/kg baicalein. Bars represent the standard de-
viation (n = 6) mary site of absorption for orally administered drugs,
CYP3A4 and P-glycoprotein are recognized as a bar-
rier to drug absorption [4, 35]. CYP enzymes signifi-
cantly contribute to first-pass metabolism and oral
bioavailability. Moreover, induction or inhibition of
Effect of baicalein on the pharmacokinetics intestinal CYP enzymes may be responsible for sig-
of iv nimodipine nificant drug-drug interactions [17], in which one
agent decreases or increases the bioavailability and
The mean arterial plasma concentration-time profiles absorption rate constant of another drug administered
of nimodipine following an intravenous administra- concurrently [11]. Therefore, dual inhibitors against
tion of nimodipine (3 mg/kg) to rats in the presence or both CYP3A4 and P-glycoprotein should have a great
absence of baicalein (0.4, 2 and 8 mg/kg) are shown impact on the bioavailability of many drugs for which
in Figure 4, and the corresponding pharmacokinetic CYP3A4 metabolism and P-glycoprotein mediated
parameters are shown in Table 2. The AUC of nimo- efflux are the major barriers to systemic availability.
dipine increased but was not statistically different With the great interest in herbal components as alterna-
than the iv control group. The T1/2 of nimodipine was tive medicines, much effort is currently being expended
also prolonged, but this increase was not significant. to identify natural compounds of plant origin that modu-
The pharmacokinetics of intravenous nimodipine late P-glycoprotein and metabolic enzymes. However,

Tab. 2. Mean pharmacokinetic parameters of nimodipine after iv administration of nimodipine (3 mg/kg) to rats with baicalein (0.4, 2 and
8 mg/kg)

Parameter Control Nimodipine with baicalein

0.4 mg/kg 2 mg/kg 8 mg/kg
AUC0–¥ (ng¡ ´ h/ml) 570 ± 118 605 ± 127 641 ± 131 675 ± 137
CLt (ml/h/kg) 87 ± 18 82 ± 17 78 ± 16 74 ± 15
T1/2 (h) 6.5 ± 1.3 6.7 ± 1.4 7.1 ± 1.5 7.2 ± 1.5
RB 100 106 112 118

The mean ± SD (n = 6), 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


there is less information on the pharmacokinetic inter- in reduced intestinal or hepatic first-pass metabolism.
actions between herbal components and medicines. These results are consistent with a report by Choi et al.
More preclinical and clinical investigations on the in- [2], which showed that morin significantly increased
teractions between herbal constituents and drugs the AUC0–¥ and Cmax of nimodipine, a P-glycoprotein
should be performed to prevent potential adverse re- and CYP3A4 substrate, and a report by Shin et al. [28],
actions in patients or to utilize those interactions for which showed that baicalein significantly increased the
a therapeutic benefit. To this end, the present study AUC0–¥ and bioavailability of doxorubin in rats.
evaluated the effect of baicalein, a naturally occurring Baicalein significantly enhanced the oral bioavail-
flavonoid, on the pharmacokinetics of nimodipine in ability of nimodipine, which might be primarily at-
rats to examine a potential drug interaction between tributable to the promotion of intestinal absorption
baicalein and nimodipine via the dual inhibition of and the reduction of first-pass metabolism of nimo-
CYP3A4 and P-glycoprotein. dipine in the intestine and/or liver via inhibition of
Nimodipine is metabolized by CYP3A4 in both the P-glycoprotein and CYP3A4.
liver and small intestine [23, 26] and the absorption of
nimodipine in the intestinal mucosa is inhibited by the
P-glycoprotein efflux pump [24]. P-glycoprotein is ex-
pressed with the glutathione-S-transferases CYP3A4 Conclusion
[29, 31], which may play a synergistic function in
regulating the bioavailability of many orally ingested
Baicalein significantly enhanced the oral bioavailabil-
compounds. In the small intestine, P-glycoprotein
ity of nimodipine, which might be mainly due to the
co-localized with CYP3A4 at the apical membrane of
inhibition of CYP3A4-mediated metabolism of nimo-
cells [35]. P-glycoprotein and CYP3A4 might act syn-
dipine in the small intestine and/or in the liver and in-
ergistically to limit oral absorption and first-pass me-
hibition of the P-glycoprotein efflux pump in the
tabolism [32]. Therefore, CYP3A4 and P-glycoprotein
small intestine by baicalein, rather than the renal
inhibitors have the potential to alter the pharmacokinet-
elimination of nimodipine. The increase in oral bioa-
ics of nimodipine. The inhibitory effect of baicalein
vailability of nimodipine in the presence of baicalein
against CYP3A4-mediated metabolism was confirmed
should be taken into consideration as a potential drug
by the use of the recombinant CYP3A4 enzyme.
interactions between nimodipine and baicalein.
As shown in Figures 1 and 2, baicalein had an in-
hibitory effect against CYP3A4-mediated metabolism
and significantly inhibited P-glycoprotein activity.
These results are consistent with a previous report References:
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