Xenobiotica

the fate of foreign compounds in biological systems

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Effect of diammonium glycyrrhizinate on

pharmacokinetics of omeprazole by regulating
cytochrome P450 enzymes and plasma protein
binding rate

Lu Han, Rong Wang, Bin Wu, Yanqiu Gu & Yongfang Yuan

To cite this article: Lu Han, Rong Wang, Bin Wu, Yanqiu Gu & Yongfang Yuan (2019)
Effect of diammonium glycyrrhizinate on pharmacokinetics of omeprazole by regulating
cytochrome P450 enzymes and plasma protein binding rate, Xenobiotica, 49:8, 975-980, DOI:
10.1080/00498254.2018.1523486

To link to this article: https://doi.org/10.1080/00498254.2018.1523486

Accepted author version posted online: 14

Sep 2018.
Published online: 21 Dec 2018.

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XENOBIOTICA
2019, VOL. 49, NO. 8, 975–980
https://doi.org/10.1080/00498254.2018.1523486

RESEARCH ARTICLE

Effect of diammonium glycyrrhizinate on pharmacokinetics of omeprazole by

regulating cytochrome P450 enzymes and plasma protein binding rate
Lu Han
, Rong Wang
, Bin Wu, Yanqiu Gu and Yongfang Yuan
Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

ABSTRACT ARTICLE HISTORY

1. In clinical practice, diammonium glycyrrhizinate is usually used with omeprazole in patients with Received 19 July 2018
viral hepatitis and cirrhosis accompanied by peptic ulcers. However, the drug interaction between dia- Revised 3 September 2018
mmonium glycyrrhizinate and omeprazole remains unclear. Accepted 10 September 2018
2. In this study, the effects of diammonium glycyrrhizinate on the pharmacokinetics of omeprazole
KEYWORDS
was investigated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method. Diammonium glycyrrhizi-
Male Sprague–Dawley rats were randomly assigned to two groups: omeprazole and omeprazo- nate; omeprazole; LC-MS/
le þ diammonium glycyrrhizinate, and the main pharmacokinetic parameters were estimated after oral MS; cytochrome P450
administration. It was found that using the omeprazole along with the diammonium glycyrrhizinate enzyme; drug interaction
increased the AUC, AUMC, Cmax for omeprazole.
3. For this reason, we used the LC-MS/MS to detect the binding rate of plasma protein (BRPP) of ome-
prazole in rats, it was found that diammonium glycyrrhizinate could decrease the BRPP in rats. In add-
ition, we found that diammonium glycyrrhizinate specifically inhibited the enzyme activity of the
CYP2C19 and CYP3A4, which are involved in the metabolism of the omeprazole.
4. These results mean that diammonium glycyrrhizinate could inhibit the metabolism and increase the
plasma concentration of the omeprazole in rats. Overall, diammonium glycyrrhizinate can influence
the pharmacokinetics of omeprazole by inhibiting CYP2C19 and CYP3A4 activities and decreasing
BRPP of omeprazole.

Introduction diammonium glycyrrhizinate and omeprazole combination

treatment could be used to repress the progression of the
Omeprazole is a proton pump inhibitor (PPI), which binds
disease. Therefore, potential pharmacokinetic interactions
covalently to the membrane-bound Hþ/Kþ ATPase
between diammonium glycyrrhizinate and omeprazole
(Mizunashi et al., 1993). Omeprazole effectively inhibits the
should be considered in this potential drug combination.
Hþ/Kþ ATPase activity of the stomach parietal cells, so that However, there are no reports about the interactions
Hþ transportation into the gastric cavity is stopped, leading between diammonium glycyrrhizinate and omeprazole.
to the reduction of gastric acid secretion at the final stage of Cytochrome P450 enzymes are the most important phase
the acid secretory pathway (Jiang et al., 2002; Tari et al., I drug-metabolizing enzyme systems in vivo, and whereby it
2001). In this way, omeprazole rapidly increases the pH level accounts 75% of drug metabolism occurring in the human
of the stomach, providing pain relief to heartburns and the body. It has been known that cytochrome P450 enzymes
stomachache, especially in dyspepsia, peptic ulcer, gastroeso- play an important role in the oxidative biotransformation of
phageal reflux and laryngeal reflux (Kiljander et al., 2000; a vast number of structurally diverse drugs (Danielson 2002;
Long & Huang, 2014; Termanini et al., 1996; Welage & Kandel & Lampe, 2014; Sridhar et al., 2012). Therefore, cyto-
Berardi, 2000). chrome P450 enzymes are critical for the pharmacokinetic
Diammonium glycyrrhizinate is an effective component behavior of most therapeutic drugs (Pergolizzi et al., 2011;
extracted from Glycyrrhiza uralensis Fisch, a herbal medicine, Tolou-Ghamari, 2012). Drug-metabolizing cytochrome P450
it has numerous pharmacological effects, involving significant enzymes are mainly composed of CYP1, CYP2 and CYP3 fam-
anti-inflammatory effects, anti-viral and hepatoprotective ilies. More specifically, the most important P450 enzymes in
activities (Li et al., 2013). This compound is used in the treat- drug metabolism are cytochrome P450 (CYP) 1A2, from the
ment of patients with human immunodeficiency virus (HIV), CYP2C family, CYP2D6 and CYP3A4 (Kinoshita et al., 2011;
chronic hepatitis A virus (HAV), hepatitis B virus (HBV), cor- Krau, 2013; Seven et al., 2014).
onavirus and herpes virus (Li et al., 2014). During chronic Proton pump inhibitors (PPIs) are used extensively in the
viral hepatitis, cirrhosis usually induces peptic ulcers, treatment of gastric acid-related disorders and are often

CONTACT Yongfang Yuan nmxyyf@126.com Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine,
280 Mo He Rd, Shanghai 201999, China
*These authors contributed equally to this work.
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
976 L. HAN ET AL.

used over long periods of time, which raises the potential for Animals
clinically significant drug interactions in patients receiving
The animal experimental protocol was approved by the
concomitant medications (Wedemeyer & Blume, 2014).
Animal Ethics Committee of the Shanghai 9th People’s
Among them, omeprazole’s plasma half-life time (T1/2) is
Hospital, Shanghai Jiao Tong University School of Medicine.
0.5–1 h, and omeprazole undergoes a first-pass metabolism
in the intestinal mucosa and/or lumen, as well as in the liver (Approval ID: 201789). Male Sprague–Dawley rats aged
(Watanabe et al., 1994). Omeprazole is nearly completely cat- 4–6 weeks, weighing 200–220 g were supplied by Shanghai
alyzed and oxidized by the liver microsomal cytochrome slake laboratory animal co. LTD. (Shanghai, China). The rats
P450 enzymes oxidase system (Sugimoto & Furuta, 2012). were maintained at 22 ± 2  C and 50 ± 10% relative humidity
From reported research, CYP2C19 and CYP3A4 are two in an air-conditioned animal quarter. Water and food (labora-
important enzymes in the degradation progress of omepra- tory rodent, Shanghai, China) were acceptable. After five
zole (Gonzalez et al., 2003). Thus, omeprazole carries a con- days of acclimation, the rats fasted for 12 h prior to
siderable potential for drug interactions because of its high each experiment.
affinity for CYP2C19 and moderate affinity for CYP3A4, and
potential drug interactions should be considered when Instrumentation and conditions
choosing omeprazole with other drugs, which can affect the
activities of cytochrome P450 enzymes. Some researchers An Agilent 1290 liquid chromatography–mass spectrometer
have indicated that diammonium glycyrrhizinate could affect was used in the study. The LC system consisted of a binary
the activity of the metabolism enzymes in the liver (Yang pump, an on-line degassing machine, an automatic sampling
et al., 2001), hence our study aims at investigating whether system and a column oven. An Agilent 6370 mass spectrom-
diammonium glycyrrhizinate influences the pharmacokinetics eter (Agilent Technologies, Santa Clara, CA, USA) equipped
of omeprazole by regulating the activities of CYP2C19 with an electrospray source was connected to the LC system.
and CYP3A4. The same LC separation conditions were used for LC-MS/MS.
Therefore, to discover the possible interactions between The Agilent MassHunter B 4.0 (Agilent Technologies) software
diammonium glycyrrhizinate and omeprazole, the effect of was performed to control the equipment and for data acqui-
diammonium glycyrrhizinate on the pharmacokinetics of sition and analysis. The sample was separated on Waters
omeprazole was investigated by liquid chromatography-tan- Xbridge C18 column (3.0  100 mm, i.d.; 3.0 lm, Milford, MA,
dem mass spectrometry (LC-MS/MS). Furthermore, we used USA) and eluted with the mobile phase: water (containing
LC-MS/MS to detect the binding rate of plasma protein 0.1% formic acid) and acetonitrile (25:80, v:v) at a flow rate
(BRPP) of omeprazole in rats. The effects of diammonium gly- of 0.3 mL/min and injection volume of 2 lL. The mass scan
cyrrhizinate on cytochrome P450 enzymes were also ana- mode was set on Multiple reaction monitoring (MRM) mode.
lyzed. This study could provide useful insight into the safe The precursor ion and product ion were m/z 345.8 ! 197.7
and effective combined usage of diammonium glycyrrhizi- for omeprazole and m/z 271.1 ! 123.0 for quinoxaline,
nate and omeprazole. respectively. The collision energy for omeprazole and qui-
noxaline were 20 and 40 eV, respectively. The mass condi-
Materials and methods tions were optimized as follows: fragmentor, 110V; capillary
voltage, 3.5 kV; nozzle voltage, 500V; nebulizer gas pressure
Materials and reagents (N2), 30 psig; drying gas flow (N2), 10 L/min; gas temperature,
Standard omeprazole (No.101163-201001, purity >98%) was 350  C; sheath gas temperature, 250  C; and sheath gas flow,
purchased from the National Institutes for Food and Drug 11 L/min.
Control (Beijing, China). Internal standard: quinoxaline (purity
>98%) was obtained from Sigma Chemical Co. (St. Louis, Preparation of standard solutions
MO). Acetonitrile was purchased from Merck (Darmstadt,
Germany) and methanol purchased from Honeywell Burdick The stock solution of omeprazole and quinoxaline were pre-
& Jackson (Maurice, NJ, USA). Omeprazole magnesium pared in methanol at a concentration of 1.00 mg/mL and
enteric-coated tablets were purchased from Astrazeneca 110 ng/mL, respectively. Then, the internal standard stock
pharmaceutical Co., Ltd (London, England). Diammonium gly- solution was further diluted to 110 ng/mL before use.
cyrrhizinate capsules were purchased from Jiangsu Zhengda Calibration standard samples for omeprazole were prepared
Tianqing Pharmaceutical Co., Ltd (Batch number: 170320, in blank rat plasma at concentrations of 2–2000 ng/mL.
Jiangsu, China). CYP inhibitors: a-naphthoflavone (a-NF,
N5757), sulfaphenazole (SUL, S0758)/CYP2C9, ticlopidine (TIC,
Preparation of rat plasma samples
T6654), quinidine (QUI, R751839), 4-methylpyrazole (4ME,
M1387), ketoconazole (KET, K1003) were purchased from To 100 mL aliquot of a plasma sample, 20 mL methanol and
Sigma Chemical Co. All other reagents and solvents were of 180 mL internal standard methanol solution (0.02 mg/mL) were
analytical reagent grade. Ultrapure water was prepared with added, then the mixture was vortexed for 30 s, and centri-
a Milli-Q water purification system (Millipore, Billerica, MA). fuged at 12,000 r/min for 10 min. The supernatant was trans-
All other chemicals were of analytical grade or better. ferred to an injection vial for LC-MS/MS analysis.
 XENOBIOTICA 977

Validation of LC–MS/MS method Inhibitory effect of diammonium glycyrrhizinate on

cytochrome P450 enzymes in vitro
Ten concentrations of calibration standards were determined
for the calibration curve as described above. The calibration The experiment was conducted according to the procedures
curves for omeprazole were constructed by plotting peak of the screening kit instructions for high-throughput cyto-
area ratios against plasma concentrations. Method specificity chrome P450 enzyme inhibitors. The reaction was initiated
was investigated by analyzing 10 individual blank rat plasma by addition of 1 mM NADPH and terminated with 2 mL
samples, which were compared with those obtained by spik- chilled ethyl acetate after 20 min incubation. A different con-
ing analytes and internal standard into the corresponding centration of diammonium glycyrrhizinate (0.78–100 lM) was
blank plasma sample to monitor interference. For the calibra- added to the final mixture as the internal standard. For the
tion curve, 10 concentrations of calibration standards (2, 5, measurement of known specific inhibitors toward the six
10, 20, 50, 100, 200, 500, 1000 and 2000 ng/mL) were proc- human hepatic CYP isoenzymes, incubations were the same
essed and determined as described above. The calibration as described above except that the mixtures also included
curves for omeprazole were constructed by plotting peak various CYP enzyme inhibitors. These inhibitors included
area ratios of the analyte to IS against plasma a-naphthoflavone (a-NF)/CYP1A2, sulfaphenazole (SUL)/
concentrations. CYP2C9, ticlopidine (TIC)/CYP2C19, quinidine (QUI)/CYP2D6,
4-methylpyrazole (4ME)/CYP2E1, ketoconazole (KET)/CYP3A4.
Negative control (solvent only) incubations were also con-
Pharmacokinetic experiment ducted. The excitation wavelength and emission wavelength
were selected according to different cytochrome P450
For the pharmacokinetic study, 12 rats were equally divided
enzymes and substrate. The excitation wavelength of 410 nm
into two groups, with 6 rats in each group, the two groups
and emission wavelength at 460 nm were used for the deter-
being omeprazole (4 mg/mL) þ diammonium glycyrrhizinate
mination of CYP1A2, the excitation wavelength of 409 nm
group (20 mg/mL) (A) and omeprazole only group (4 mg/mL)
and emission wavelength at 530 nm were used for the deter-
(B). The omeprazole magnesium enteric-coated tablets were
mination of CYP2C9, the excitation wavelength of 410 nm
dissolved in distilled water, methylcellulose was added and
and emission wavelength at 460 nm were used for the deter-
dispersed evenly. Diammonium glycyrrhizinate capsules were
mination of CYP2C19, and the excitation wavelength of
homogenized in water solution. Diammonium glycyrrhizinate
409 nm and emission wavelength at 538 nm were used for
was administrated to rats in group A at a dose of 100 mg/kg
the determination of CYP3A4. Residual activity of diammo-
per day for 7 days, and an equal amount of distilled water
nium glycyrrhizinate corresponding concentration (%) was
was given in group B once a day for 7 days. After the rats in
calculated based on the fluorescence intensity value of 96-
both groups were gavaged with diammonium glycyrrhizinate
hole plate read out in the fluorescence scanner. IC50 was cal-
solution and distilled water, respectively, omeprazole was
culated by plotting the residual activity with the correspond-
administered at a dose of 20 mg/kg after 1 h. Blood samples
ing value of sample concentration.
(0.5 mL) were collected into a heparinized tube through the
oculi choroidea vein before drug administration and at 0.25,
0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 and 24 hours after drug adminis- Plasma protein binding rate
tration. After centrifuging at 3500 r/min for 5 min, the super-
Experimental data sets used in this study were collected
natant was obtained and frozen at –80  C until analysis.
from the literature (Ma et al., 2008). Drugs in these data sets
have been carefully checked to eliminate duplication. The
protein binding rates of diammonium glycyrrhizinate, ome-
Pharmacokinetic analysis
prazole, diammonium glycyrrhizinate þ omeprazole with rat
DAS version 3.0 (BioGuider Co., Shanghai, China) was used to plasma were investigated. Three kinds of mass concentra-
analyze the plasma pharmacokinetic data and calculate the tions (25, 50, 100 lg/mL) were prepared using phosphate
parameters. The maximum plasma concentration (Cmax) and buffer with the pH of 7.14 for each combination, respectively.
the time taken for the drug to reach Cmax (Tmax) were Each solution was carefully poured into an Eppendorf centri-
obtained directly from the concentration–time curves. The fuge tube, rat plasma was added and mixed evenly, then
linear regression of plasma concentration and time was cal- incubated at 37  C for 20 min. Then centrifuged at 7200
culated by the linear regression method, and the elimination r/min in an ultrafiltration pipe for 15 min. The concentration
rate constant (k) was calculated. The elimination half-life of omeprazole in rat plasma was measured by LC-MS/MS
(t1/2) was calculated from the formula t1/2 ¼ 0.693/k. The lin- analysis, and the plasma protein binding rate was calculated
ear trapezoidal rule (AUC0–t) was used to calculate the area by substituting it into the standard curve. PPBR (%) ¼ (Total
under the concentration–time curve. The mean residence plasma mass concentration–Free mass concentration)/Total
time (MRT) was calculated with AUMC0–1/AUC0–1, whereby plasma mass concentration 100%. The actual class of drugs
AUMC0–1 represented the area under concentration–time was identified based on its relative value of plasma protein
curve since the initiation of the experiment. All data were binding rate: positively assigned if its plasma protein binding
presented as mean ± SD. rate 75%, negative assigned otherwise.
978 L. HAN ET AL.

Figure 1. Representative multiple reaction monitoring chromatogram of (A) blank plasma, (B) blank plasma spiked with 1) omeprazole and 2) internal standard:
quinoxaline.

Statistical analysis
All experiments were performed in triplicate and the data
were expressed as the mean ± SD. Unless stated otherwise,
the statistical analysis was performed using GraphPad Prism
5.01 (San Diego, CA) and comparisons between two groups
were conducted with a t-test. Observed differences were
considered statistically significant if p < .05.

Results and discussion

Method feasibility verification
For the calibration curve, ten concentrations of calibration Figure 2. The time-dependent curves of mean concentration of omeprazole in
standards (2, 5, 10, 20, 50, 100, 200, 500, 1000 and 2000 ng/ rat plasma samples, which were extracted from rats that were orally adminis-
mL) were processed and determined as described above. The trated with diammonium glycyrrhizinate and omeprazole (group A) or only
omeprazole (group B) (n ¼ 6).
calibration curves for omeprazole were constructed by plot-
ting peak area ratios of the analyte to quinoxaline against
plasma concentrations. The lower limit of quantification
(LLOQ) was determined as the concentration of the analyte
Effects of diammonium glycyrrhizinate on the
with a signal-to-noise ratio of 10. In the present study, the
pharmacokinetics of omeprazole in rats
selectivity was examined by independent plasma samples
from six different rats. As shown in Figure 1, no obvious The effects of diammonium glycyrrhizinate on the pharmaco-
interference was observed in the representative chromato- kinetics of omeprazole in rats were then evaluated. The con-
gram of a blank plasma sample at the retention times of the centration of omeprazole in rat plasma was determined by
analyte and IS, which indicated that the LC-MS/MS method LC-MS/MS method as described above. The time-dependent
for the quantification of omeprazole was sensitive and feas- curves were shown in Figure 2, and the pharmacokinetic
ible enough for the pharmacokinetic studies with rat plasma. parameters were calculated by Das 3.0 software (Shanghai
 XENOBIOTICA 979

Table 1. Main pharmacokinetics parameters of omeprazole in rats (n ¼ 6).

Parameter Unit Omeprazole Omeprazole þ diammonium glycyrrhizinate
AUC(0-t) lg/L  h 1441.96 ± 67.01 2345.36 ± 229.87#
AUC(0-1) lg/L  h 1471.79 ± 67.15 2355.74 ± 230.48#
AUMC(0-t) h  hlg/L 2737.68 ± 188.50 4631.43 ± 498.74#
AUMC(0-1) h  hlg/L 3037.13 ± 213.69 4754.19 ± 508.22#
MRT(0-t) h 1.90 ± 0.06 1.97 ± 0.02
MRT(0-1) h 2.06 ± 0.08 2.02 ± 0.03
t1/2z h 1.40 ± 0.07 1.25 ± 0.07
Tmax h 0.5 ± 0 0.75 ± 0
CLz/F L/h/kg 1.36 ± 0.06 0.86 ± 0.09#
Cmax lg/L 836.57 ± 83.85 1326.51 ± 118.99#
#p < .05 compared with omeprazole group.

Table 2. Inhibitory effect of diammonium glycyrrhizinate on CYP450 in vitro (%).

Enzymatic activity (n ¼ 3)
Concentration (lmol/L) CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4
100 89.87 ± 3.23 78.98 ± 0.97 5.12 ± 0.34 65.87 ± 2.94 5.65 ± 0.24
50 88.95 ± 2.87 79.09 ± 3.16 10.98 ± 3.49 76.98 ± 6.18 5.34 ± 0.75
25 95.76 ± 5.19 86.98 ± 4.16 28.56 ± 3.59 77.98 ± 1.28 10.87 ± 1.20
12.5 95.44 ± 3.21 84.23 ± 4.27 58.87 ± 3.29 85.32 ± 1.76 20.87 ± 1.46
6.25 96.88 ± 4.29 95.98 ± 4.31 69.09 ± 1.29 86.65 ± 1.87 37.65 ± 2.39
3.13 97.98 ± 1.29 92.13 ± 2.97 76.90 ± 4.26 90.90 ± 4.59 47.09 ± 1.29
1.56 98.43 ± 0.98 99.08 ± 3.89 85.98 ± 0.79 91.87 ± 2.37 79.76 ± 3.78
0.78 99.07 ± 3.17 95.34 ± 4.56 90.34 ± 1.59 92.65 ± 1.29 90.98 ± 2.91
IC50 >100 >100 17.78 ± 1.34 >100 3.56 ± 0.72

BioGuider Medicinal Technology Co. Ltd, Shanghai, China) omeprazole in the human body. These results demonstrated
and shown in Table 1. that diammonium glycyrrhizinate can inhibit the metabolism
As shown in Figure 2, the mean plasma concentration of of omeprazole through regulating CYP2C19 and CYP3A4
omeprazole was much higher in group A than that in group enzymes activities, further indicating that diammonium gly-
B. As shown in Table 1, the parameter values of AUC, AUMC, cyrrhizinate might inhibit CYP2C19-mediated omeprazole
Cmax for omeprazole in group A were much higher than hydroxylation (Chang et al., 1995) and CYP3A4-mediated
those in group B, which suggested that diammonium glycyr- omeprazole sulfone formation (Fan et al., 2007).
rhizinate can prolong the circulation time and increase the
concentration of omeprazole in rats. A possible reason may
be that diammonium glycyrrhizinate decreases the BRPP of Effects of diammonium glycyrrhizinate on the BRPP
omeprazole and increases the concentration of free omepra- of omeprazole
zole in rat plasma; or that diammonium glycyrrhizinate might
As omeprazole in combination with diammonium glycyrrhizi-
inhibit the metabolism of omeprazole, increasing the accu-
nate could obviously increase the Cmax of the omeprazole in
mulation of omeprazole in vivo. For this reason, we further
blood, we extrapolated that perhaps diammonium glycyrrhi-
used the LC-MS/MS to detect the binding rate of plasma pro-
zinate could decrease the BRPP of omeprazole, thus increas-
tein (BRPP) of omeprazole in rats. In addition, effects of dia-
ing the concentration of free omeprazole in rat plasma. We
mmonium glycyrrhizinate on activities of the cytochrome
then evaluated the BRPP of omeprazole in the combined
P450 enzymes were detected according to screening kit
instructions for high-throughput cytochrome P450 enzymes drug group, and the results are shown in Table 3. From
enzyme inhibitors. Table 3, it can be seen that diammonium glycyrrhizinate has
obviously decreased the BRPP of omeprazole, which con-
firmed our hypothesis.
Effects of diammonium glycyrrhizinate and omeprazole Therefore, there may be potential interactions between
inhibition on cytochrome P450 enzymes diammonium glycyrrhizinate and omeprazole in clinical appli-
According to the pharmacokinetics study, we can see that cations. It is also possible that administration of diammo-
the diammonium glycyrrhizinate can increase the bioavail- nium glycyrrhizinate in a clinical setting may result in the
ability of the omeprazole. To further clarify the mechanisms accumulation and increased concentration of omeprazole, by
of the drug interaction between diammonium glycyrrhizinate inhibiting the metabolism or the BRPP of omeprazole. Thus,
and omeprazole, we analyzed the effects of diammonium more attention should be paid when using diammonium
glycyrrhizinate on the activities of cytochrome P450 enzymes. glycyrrhizinate and omeprazole together.
The enzyme activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6
and CYP3A4 (Table 2) have all been tested in this study.
Conclusion
From Table 2, we can see that diammonium glycyrrhizinate
showed some specific inhibition of CYP2C19 and CYP3A4, Detection of the concentration of omeprazole in rat plasma
which are the two major metabolic enzymes of the by the LC-MS/MS method showed that using omeprazole in
980 L. HAN ET AL.

Table 3. Plasma protein binding rates of omeprazole and diammonium glycyrrhizinate (n ¼ 3).
Sample group Total plasma mass concentration (lg/mL) Free mass concentration (lg/mL) Plasma protein binding rate (%)
Diammonium glycyrrhizinate 25 1.05 ± 0.12 95.8 ± 0.48
50 2.54 ± 0.34 94.92 ± 0.68
100 6.08 ± 1.27 93.92 ± 1.27
Omeprazole 25 1.87 ± 0.16 92.52 ± 0.64
50 2.76 ± 0.49 94.48 ± 0.98
100 6.58 ± 0.97 93.42 ± 0.97
Omeprazole (diammonium glycyrrhizinate) 25 6.71 ± 0.49 73.16 ± 1.96
#
50 12.83 ± 0.99 74.34 ± 1.98
#
100 24.97 ± 2.31 75.03 ± 2.31
#

p < .05 compared with diammonium glycyrrhizinate; #p < .05 compared with omeprazole.

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Disclosure statement Pergolizzi JV, Labhsetwar SA, Puenpatom RA, et al. (2011). Prevalence of
exposure to potential CYP450 pharmacokinetic drug-drug interactions
No potential conflict of interest was reported by the authors. among patients with chronic low back pain taking opioids. Pain
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Funding phisms of cytochrome P450 CYP2C9, CYP2C19, and CYP2D6 on drug-
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and Health Foundation [YWJK JJHK YJJ-A711, B17536] and the Fund of chrome p450 enzymes and inhibitors obtained through QSAR studies.
Shanghai Pharmaceutical Association [2017-YY-02-11]. Molecules 17:9283.
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