Original Article

Yonago Acta medica 2016;59:111–117

Pharmacokinetic Interaction Study of Ranitidine and Daijokito in Healthy
Volunteers
Yusuke Endo,* Yoshitaka Ishihara,* Satoshi Tsuno,* Akiko Matsuda,† Weibin Qian,* Norimasa Miura* andJunichi Hasegawa**Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine,
Yonago 683-8503, Japan and †Department of Fundamental Nursing, School of Health Science, Tottori University Faculty of Medicine,
Yonago 683-8503, Japan

ABSTRACT

Key words

Backgrounddaijokito; drug-drug interaction; pharmacokinetics; ranitidine

Corresponding author: Yusuke Endoy-endo@med.tottori-u.ac.jp
Received 2016 January 15
Accepted 2016 February 5
Abbreviations: AE, adverse experience; AUC, area under the plasma concentration-time curve; AUC0–12, area under the plasma concentration-time curve from 0 to 12 h; BMI, body mass index; CI,
confidence interval; Cmax, maximum plasma concentration; CYP,
Cytochrome P450; FMO, flavin-containing monooxygenase; GER,
gastric emptying rate; GM, geometric mean; ke, elimination rate
constant; %CV, percent coefficient of variance; Tmax, time to reachmaximum plasma concentration; t1/2, elimination half-life

Ranitidine is a histamine 2 receptor antagonist that is
widely used in the treatment of peptic ulcer, gastric mucosal lesion and in the control of acid secretion.1, 2 In
addition, ranitidine is given as a proprietary drug for
gastric pain and a heavy feeling in the stomach. It isalso thought that the excretion amount of ranitidine unchanged body in urine is large, and ranitidine pharmacokinetic is influenced by renal function in the process of
excretion. In cases like this, the dose of ranitidine should
be adjusted depending on renal function.3
Daijokito is a Kampo formula, which is traditionallyused as a purgative for clearing internal heat in the stomach and intestines and treating constipation.4, 5 It is composed of magnolia bark (Magnolia officinalis), rheum(Rheum), bitter orange (Citrus aurantium) and sodium
sulfate.
Kampo formulas play an important role in modern
medicine and are sometimes the preferred choice in an
effective therapeutic approach to diseases that cannot be
identified by a single etiology. According to the questionnaire, approximately 80% of physicians use Kampo
formulas in general practice.6 Although concomitanttherapy using western medicine and Kampo formulas isoften provided for the purpose of enhancing therapeutic efficacy and decreasing the side effects,7, 8 there isinsufficient information in the exact use or interactionof these therapies at the present time. A few studies
have reported that Kampo formulas had some effect on
the pharmacokinetics of drugs such as Warfarin and
Ticlopidine hydrochloride.9, 10 Some studies focusing
on the pharmacokinetic interaction between ranitidine
and other medicines have been reported.11 Even though
there were no serious adverse interactions between the
drugs and herbal prescription medications in patients,12
there were still life-threatening herb-drug interactions inrats.13
Ranitidine is also used as an over-the-counter (OTC)
drug and there are possibilities of its administration withdaijokito in clinical practice. In an earlier preclinicalRanitidine is a histamine 2 receptor antagonist, and daijokito is a Kampo (Chinese herbal medicine as practiced in Japan) formula, which is traditionally used for treating constipation and digestive trouble.
Previous study demonstrated that daijokito significantly
affected the pharmacokinetics of ranitidine in rats; however, the doses of ranitidine and daijokito in that study
were higher than in clinical practice. Therefore, we examined the pharmacokinetic interaction between ranitidine and daijokito in clinical practice doses in healthy
volunteers.
Methods This was a randomized, open label, two-period crossover study in healthy volunteers (n = 7). Volunteers received administrations of either a single dose ofranitidine 300 mg, or ranitidine 300 mg in combination
with daijokito extract granules 2.5 g. Plasma concentrations of ranitidine were measured over 12 h by LC/MS/
MS method.
Results Plasma concentrations of ranitidine werelower with co-administration of daijokito comparedwith ranitidine alone. Co-administration of daijokito
significantly decreased ranitidine area under the plasma
concentration-time curve from 0 to 12 h (AUC0–12) andmaximum plasma concentration (Cmax) with geometricmean (GM) ratio [90% confidence interval (CI)] for
AUC0–12 of 0.609 (0.449, 0.826) and Cmax of 0.515 (0.345,
0.771).
Conclusion Co-administration of ranitidine with daijokito resulted in a significant decrease in plasma levelof ranitidine in healthy volunteers.

111

Y. Endo et al.

study of rats, when ranitidine and daijokito were co-administered, ranitidine plasma concentration was lower,
and ranitidine t1/2 was also delayed. It was demonstrated
that daijokito significantly affected the pharmacokineticsof ranitidine.14 However, the doses of ranitidine and daijokito in this study were higher than in the human clinical setting, and it remains unclear whether the clinicalpractice dose of daijokito influenced the pharmacokinetics of ranitidine. The aim of this study was to evaluate
the pharmacokinetic interaction between ranitidine anddaijokito in a clinical practice dose in healthy volunteers
in order to establish the potential clinical relevance of apreclinical study.

Trials Registry (UMIN000013106), and was conductedin accordance with the ethical principles established in
the Declaration of Helsinki and consistent with Ethical
Guidelines for Clinical Research.
Study design and treatment

This study was a randomized, open label, two-period
crossover design with two periods that were separated
by at least a 5-day washout period (Fig. 1). During thestudy, volunteers received administrations of either
ranitidine 300 mg (Treatment I), or ranitidine 300 mg incombination with daijokito extract granules 2.5 g (Treatment II) with water during fasting. Ranitidine (Zantac
150 mg tablet) and daijokito extract granules 2.5 g werepurchased from GlaxoSmithKline & Co. (Tokyo, Japan)
and Tsumura & Co. (Tokyo, Japan), respectively. For
pharmacokinetic analyses of ranitidine, blood samples
were collected at pre-dose and 0.5, 1, 1.5, 2, 4, 8 and 12
h post-dose on Day 1. Venous blood (5 mL) was collected into tubes and plasma samples were separated bycentrifugation at 1,500 g and 4 °C for 10 min and stored
frozen at –30 °C until analyzed. Urine samples also werecollected at pre-dose (spot urine) and 0–12 h post-dose(pooled urine), and samples were immediately stored
frozen at –30 °C until analyzed.

MATERIAL AND METHODS
Study population

The study was conducted in healthy male volunteers,
20–23 years old. Physical examination, laboratory tests
and vital signs were conducted at screening. Volunteers
with diarrhea, abnormalities in laboratory tests or drug
hypersensitivity were excluded from this study. All
volunteers provided written, informed consent prior
to study initiation and final protocol was approved by
Ethics Review Committee of Tottori University, Faculty of Medicine in Japan (Approval No. 1955). Thisclinical study was registered with the UMIN ClinicalFig. 1. Study design. Treatment I: Ranitidine 300 mg, Treatment II: Ranitidine 300 mg in combination with daijokito extract
granules 2.5 g.

LC/MS/MS method for ranitidine°C methanol were added in 1 volume of urine sample,
and vortex, then centrifugation at 15,000 rpm and 4 °C
for 17 min. Upper phase samples were diluted by adding
water at 40,000 times. The calibration curves for plasma
and urine by absolute calibration curve method were linear over the concentration range of 0.01 to 10.00 ng/mL (r= 0.9998 for plasma and r = 0.9999 for urine)

Concentrations of ranitidine in plasma and urine were
determined using validated liquid chromatography withtandem mass spectrometry (LC/MS/MS) method (ABSCIEX QTRAP 5500; Takara Bio, Kusatsu, Japan). For
plasma sample preparation, 3 volume of 0 °C methanol
were added in 1 volume of plasma sample, and vortex,
then centrifugation at 15,000 rpm and 4 °C for 17 min.
Upper phase samples were diluted by adding water at
400 times. For urine sample preparation, 3 volume of 0

Pharmacokinetics analysis

Pharmacokinetic parameters of ranitidine were esti112

Fi

Interaction of ranitidine and daijokito

mated by non-compartmental methods using Microsoft
Excel. The maximum plasma concentration (Cmax) andtime to maximum plasma concentration (Tmax) weredirectly obtained from the observed concentration-time
data. The area under the plasma concentration-time
curve (AUC) from zero point to last collection [areaunder the plasma concentration-time curve from 0 to 12h (AUC0–12)] was calculated according to the liner trapezoidal rule. The terminal elimination rate constant (ke)was estimated by liner terminal of the terminal portionof the In (concentration)-time curve, and the elimination
half-life (t1/2) was calculated as 0.693/ke accordingly.

Table 1. Baseline characteristics
Panel 1 (n = 4)
(Treatment I to
Treatment II)

Panel 2 (n = 3)
(Treatment II to
Treatment I)

21.8
1.1
20
23

20.7
0.5
20
21

170.0
4.1
164.0
175.0

171.0
0.8
170.0
172.0

56.0
4.7
50.0
63.0

64.7
7.4
58.0
75.0

19.3
1.0
18.3
20.6

22.1
2.7
19.6
26.0

4 (100%)3 (100%)4 (100%)3 (100%)Age (years)
AverageSD
Minimum
Maximum
Height (cm)AverageSD
Minimum
Maximum
Weight (kg)
AverageSD
Minimum
Maximum
BMI
AverageSD
Minimum
Maximum
Concomitant disease
None
Prior therapy
None
BMI, body mass index.

Safety and tolerability

Safety and tolerability were evaluated by monitoring theadverse experiences (AEs). Clinical laboratory assessment (clinical chemistry, hematology and urinalysis),vital signs and physical examination were performed atscreening, pre-dose of first administration and end of
study.
Statistical analysis

Summary statistics including geometric mean (GM),percent coefficient of variance (%CV), median, minimum and maximum were provided for ranitidine pharmacokinetic parameter. The differences of mean of
log-transrated Cmax, AUC0–12, t1/2 and urinary excretion
between the ranitidine plus daijokito and ranitidine alone
were back-transformed to estimate the GM ratios with
the 90% confidence interval (CI). Tmax, t1/2 and urine excretion rate were compared using paired t test. Microsoft
Excel was used to perform all statistical analyses.

h, and was comparable with ranitidine alone (3.23 h). In
addition, median ranitidine Tmax for co-administrationof daijokito was 2.0 h, and slightly decreased comparedwith ranitidine alone (4.0 h).

RESULTS
Demographics and baseline characteristics

Ranitidine urinary excretion

A total of 13 healthy male subjects submitted to ascreening test, and 7 subjects were enrolled in this study.
All of them completed the study without any deviation
to the protocol and therefore used for pharmacokinetic
analysis set. Four and 3 subjects were enrolled in Panel
1 and 2, respectively. Baseline characteristics of each
Panel are shown in Table 1, and there were no differences between Panels.

Ranitidine is the drug of renal excretion type, so weevaluated ranitidine urinary excretion. GM (%CV) ofranitidine urine output for co-administration of daijokito was 14.2 mg (21.7), and significantly lower thanranitidine alone [29.3 mg (21.1)]. The rate of ranitidine
excreted in urine for 12 h was significantly lower withco-administration of daijokito than ranitidine alone (Fig.
4).

Ranitidine pharmacokinetic parameters

Safety and tolerability

Plasma concentrations of ranitidine were lower withco-administration of daijokito compared with ranitidine
alone (Fig. 2). Co-administration of daijokito significantly decreased ranitidine AUC0–12 and Cmax with GM
ratio (90% CI) for AUC0–12 of 0.609 (0.449, 0.826) andCmax of 0.515 (0.345, 0.771) (Table 2 and Fig. 3). GM of
ranitidine t1/2 for co-administration of daijokito was 3.72

One subject who enrolled in Panel 1 (Treatment I to
Treatment II) reported leucocyte increase at 12 h postdose of Treatment II. Intensity was judged mild by theinvestigator. There were no clinically significant changes
in other clinical laboratory assessments (clinical chemistry, hematology and urinalysis), vital signs or physicalexamination in either Panel.
113

Fig.	  2	Y. Endo et al.
Plasma ranitidine concentration (ng/mL)

ACU0–12

Time (h)Fig. 2. Plasma concentration-time profiles of ranitidine. Open circles indicate the single dose of ranitidine (n = 7), and solid circles
indicate co-administration of ranitidine and daijokito (n = 7). Eachvalue is the mean value ± SD.

Cmax

1.2

1.2

1.0

1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0.0

0.0

Fig. 3. Ratios of ranitidine AUC0–12 and Cmax in each subject(ranitidine + daijokito/ranitidine) (color circles), and GM ratio and
90% CI (black circles).
AUC0–12, area under the plasma concentration-time curve from 0
to 12 h; CI, confidence interval; Cmax, maximum plasma concentration; GM, geometric mean.

Table 2. Pharmacokinetic parameters of ranitidine with and without daijokito
Pharmacokinetic parameters*

Ranitidine alone (n = 7)

Ranitidine + daijokito (n = 7)

GM ratio (90% CI)†

6917.7 (35.5)
3773.8 (23.4)
0.609 (0.449, 0.826)
AUC0–12 (ng h/mL)
1110.5 (55.1)
572.4 (43.1)
0.515 (0.345, 0.771)
Cmax (ng/mL)
3.23 (24.0)
3.72 (27.3)
NA
t1/2 (h)Tmax (h)4.0 (2.0–4.0)
2.0 (1.5–4.0)
NA*Values are GM (%CV) for AUC0–12, Cmax and t1/2; median (range) for Tmax.
†GM ratio = ranitidine + daijokito/ranitidine.
AUC0–12, area under the plasma concentration-time curve from 0 to 12 h; CI, confidence interval; Cmax, maximum plasma concentration;GM, geometric mean; NA, not applicable; %CV, percent coefficient of variance; Tmax, time to maximum plasma concentration; t1/2, elimination half-life.

Urinary excretion rate (%)

40
35
30
25
20
15
10
5
0

Ranitidine alone

Ranitidine + Daijokito

Fig. 4. GM (± SD) of the rate of ranitidine excreted in urine for 12 h. *P < 0.05 vs.
ranitidine alone. GM, geometric mean.

114

Interaction of ranitidine and daijokito

DISCUSSIONThe GM ratios (ranitidine + daijokito/ranitidine) (90%CI) of AUC0–12 and C max were 0.609 (0.449, 0.826)
and 0.515 (0.345, 0.771), respectively, and statisticalsignificance was demonstrated. In an earlier preclinicalstudy of rats, ranitidine mean concentration was 16.315
and 1.455 μg/mL corresponding to ranitidine alone andranitidine with daijokito, respectively, while ranitidine
AUC0–12 was also 28.083 and 9.826 μg/L h, respectively.14 These clinical study results were consistent with thesame previous preclinical study in rats,14 and showed thepossibility of drug-drug interaction between ranitidine
and daijokito in a clinical practice dose. In this study,
plasma concentrations of ranitidine were lower withco-administration of daijokito compared with ranitidine
alone, although inter-individual variability was wide. It
has been reported that the effect of ranitidine on acidsecretion does not show any significant variability, butinter-individual variability in bioavailability is wide.15 It
has been also reported that a long antisecretory activityof ranitidine was observed, although the short half-life of
the drug varies between 2 and 8 h.15 Additionally, it has
been reported that ranitidine concentrations that produce
50% of the maximal effect are about 100 ng/mL andthe maximal effect is reached at concentrations of about
600 ng/mL.16 Ranitidine t1/2 was comparable between
ranitidine alone and co-administration with daijokito,
and ranitidine Tmax under co-administration of daijokito
slightly decreased compared with ranitidine alone in thisstudy. In contrast to those data, after the addition of daijokito, ranitidine Tmax was delayed with a longer half-life
compared with ranitidine alone in rats.14
Ranitidine is affected by the first pass effect,17 and it
is metabolized to its N- and S-oxides almost exclusively(more than 93%) by flavin-containing monooxygenase(FMO) and to desmthylranitidine by cytochrome P450
(CYP) 2C19, 1A2 and 2D6.18 Kampo formulas affectcytochrome P450 and then change the process of concomitant drug metabolism.19, 20 However, there is noreport that daijokito could induce the activity of FMO,CYP2C19, 1A2 and 2D6 which metabolize ranitidine.
In addition, the ranitidine elimination rate constant(ke) of each subject in beta phase were similar between
ranitidine alone and ranitidine with daijokito in thisstudy; therefore we think that pharmacokinetic interaction might not be caused in the metabolism or excretion
phase.
In this study, ranitidine AUC0–12 was lower withco-administration of daijokito compared with ranitidine
alone. In addition, the rate of ranitidine excreted in urine
for 12 h was significantly lower with co-administrationof daijokito than ranitidine alone, and this is thought tobe due to a low ranitidine absorption rate under co-administration of ranitidine and daijokito. Ranitidine t1/2
was comparable between ranitidine alone and co-administration with daijokito. Therefore, it seems more likelythat the process of absorption can be an influence toranitidine pharmacokinetics under the co-administrationof daijokito.
Pharmacokinetic interaction in the absorption process is caused by complex formation, change of pH in
the stomach, gastrointestinal tract motility change, andtransporter-mediated mechanism. Change in gastrointestinal tract motility is one of the main factors, andit depends on changes in gastric emptying rate (GER).
In general, GER is increased, and then absorption rate
becomes faster, while the amount of absorption is increased. Kampo formulas like rikkunshito and hangesyashinto have the effect of accelerating the gastrictract,32 and the amount of concomitant drug that isabsorbed from the intestine is changed. The absorbed
amount of ranitidine for 12 h was decreased underco-administration of daijokito in this study, and daijokito is used for constipation and might change the abilityof gastrointestinal tract motility; therefore the possibility
that GER might be changed cannot be denied.
In the intestine, both P-glycoprotein and CYP3A4
are expressed in epithelial cells and cooperatively
work as a barrier to orally administered drugs. Most
substrates of CYP3A4 and P-glycoprotein overlap andthese two proteins together function as an absorption
barrier against xenobiotics by their coordinate tissue
localization and co-inducibility.21 The administration of
P-glycoprotein or CYP3A4 substrates with their othersubstrates, such as talinolol, digoxin, midazolam change
the absorbed amount or maximum concentration ofsubstrates.22–24 These are typical examples of pharmacokinetic interaction in intestinal drug absorption. In
addition, some furanocoumarins in grapefruit affect theactivities of P-glycoprotein and/or CYP3A4, resulting inalteration of the pharmacokinetics of western drugs.25
Ranitidine is a P-glycoprotein substrate, and it was foundthat oral bioavailability of ranitidine was influenced at
the intestinal absorption phase.26 P-glycoprotein is a
170–180 kDa membrane glycoprotein that mediates theactive, outward transport of a variety of mainly lipophilic compounds from cells.27 P-glycoprotein is also widely
expressed in normal tissues, including epithelial cells in
the gastrointestinal tract and kidney tubules and endothelial cells at the blood-brain barrier.28, 29 Ranitidine
could act as a substrate for intestinal P-glycoprotein andit has been suggested that the balance between absorption and secretory mechanisms is a factor in determining intestinal absorption needs as a routine consideration
115

Y. Endo et al.

even for compounds expected to have a predominantly
paracellular route of absorption.30 Ranitidine and daijokito were administered simultaneously, so it is thoughtthat pharmacokinetic interaction via p-glycoprotein
activation by daijokito could not be induced; however
Yu CP et al. reported that rheum, one of component of
daijokito, activated the function of p-glycoprotein.31
Co-administration of ranitidine and daijokito waswell tolerated, and no safety issues were identified
during the study. One subject who enrolled in Panel
1 (Treatment I to Treatment II) reported leucocyte increase at 12 h post-dose of Treatment II. The AE wasminimal deviation of reference interval, and might bedue to dehydration.
In summary, although the pharmacokinetic interaction of ranitidine and daijokito were demonstrated inthis study, only a single dose of ranitidine and daijokito
was evaluated. Therefore further data is needed to extrapolate more evidence in clinical practice. However,these data call attention to the risk of ineffectiveness ofranitidine in concomitant use of ranitidine and daijokito
in clinical practice.

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14 Wen-Fu Ta ng, Mei-Hu a Wa n, Q iao -Rong Hu a ng,
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15 Castañeda-Hernández G, Flores-Murrieta FJ, Granados-Soto V,
Herrera-Abarca A, Pérez-Urizar J, Herrera JE et al. Pharmacokinetics of oral Ranitidine in Mexicans. Arch Med Res.
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16 Franco C, Flores-Murrieta FJ, Castañeda-Hernández G. Pharmacokinetic-pharmacodynamic modeling of oral Ranitidine:
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17 Van Hecken AM, Tjandramaga TB, Mullie A, Verbesselt R,
De Schepper PJ. Ranitidine: single dose pharmacokinetics
and absolute bioavailability in man. Br J Clin Pharmacol.
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PMID: 11128045.
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20 Lau C, Mooiman KD, Maas-Bakker RF, Beijnen JH,
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Acknowledgments: We thank Katsumi Nagata at Research Center
for Bioscience and technology, Tottori University for plasma andurine ranitidine measurement. We are grateful to the volunteers
who participated in this study. In addition, we would like to express our sincere appreciation for the research grant from the Japan Research Foundation of Clinical Pharmacology (JRFCP).
The authors declare no conflict of interest.

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