Chinese Medicine, 2011, 2, 58-61
doi:10.4236/cm.2011.22011 Published Online June 2011 (http://www.SciRP.org/journal/cm)
Rikkunshi-to Partially Reverses Cancer
Chemotherapy-Induced Decrease in Plasma Valproic Acid
Concentration in a Patient with Malignant Ly mphoma
Masashi Ishihara1, Kiyoyuki Kitaichi1, Katsuhiko Matsuura1, Hiroshi Nakamura2,
Hisashi Tsurumi2, Hisataka Moriwaki2, Yoshinori Itoh1*
1Departme n t of Pharmacy, Gifu University Hospital, Gifu, Japan
2First Department of Internal Medicine, Gifu University Graduate School of Medicine,
Gifu, Japan
Received April 6, 2011; revised April 28, 2011; accepted April 29, 2011
Abstract
A fifty-five-year-old male patient with malignant lymphoma who took oral valproic acid (VPA) tablets and
itraconazole (ITZ) capsles received 3 courses of cancer chemotherapy, including 2 courses of a combination
of rituximab/methotrexate/ifosphamide/etoposide/carboplatin/ methylpredonisolon (R-IMVP16/CBDCA re-
gimen) and subsequent one course of a combination of rituximab/ranimustine/citara bine/etoposide/merpha-
lan (R-MEAM regimen). Plasma concentration of VPA dramatically decreased below the therapeutic con-
centration after the first and second chemotherapy and seizures appeared in both cases. Plasma concentration
of ITZ was also lowered after the second chemotherapy course. At the third chemotherapy, Rikkunshi-to, a
Japanese herbal medicine, was prescribed for 14 days. Plasma VPA concentration decreased, though to a
lesser extent, after chemotherapy, in which the level was near the border of therapeutic concentration. No
convulsion was observed. Therefore, care should be taken to monitor plasma drug concentration during can-
cer chemotherapy. Rikkunshi-to may be useful to alleviate the chemotherapy-induced decrease in plasma
concentrations of orally administered drugs.
Keywords: Cancer Chemotherapy, Malignant Lymphoma, Valproic Acid, Therapeutic Drug Monitoring,
Convulsion, Ri kk un sh i- to
1. Introduction
Valproic acid (VPA) has a broad spectrum of inhibitory
activity in various types of epilepsy. Furthermore, the
compound is used as a therapeutic agent for manic state
of the bipolar disorder. However, there are individual
differences in the absorption, distribution, metabolism,
excretion, and thus pharmacokinetic parameters, includ-
ing the maximum drug concentration time and half-life,
of VPA. Therefore, individual monitoring of plasma
concentration of VPA is required to determine the dosing
schedule of VPA [1,2]. The effective plasma concentra-
tion of VPA is reported to be 50 - 100 g/ml [3,4] or 40 -
120 g/ml, according to the manufacturer’s instruction.
When the plasma concentration exceeds 100 g/ml, the
incidence of the hepatic dysfunction is heightened [3].
Thus, it is important to maintain the optimal plasma
concentrat ion of VPA.
It has been reported that several compounds exhibit
pharmacokinetic interactions with VPA, which includes
carbapenem antibiotics [5-8], lamotrigine [9], salicylic
acid [10,11], benzodiazepines [12] and anticancer drugs
[13]. Ikeda et al. [13] reported a reduction of plasma
concentration of VPA in a patient who received cancer
chemotherapy regimen including cisplatin.
We reported here a case of marked decrease in plasma
VPA concentration after combination cancer chemo-
therapy with episodes of epileptic seizures. In addition,
the usefulness of a herbal medicine Rikkunshi-to was
subsequently discussed.
2. Methods
A male fifty-five-year-old patient who had recurrent
CD20- positive diffuse larg e B-cell lymphoma (DLBCL)
was a subject of the present study. Data were obtained

M. ISHIHARA ET AL.
59
from the record of pharmaceutical practices in hematol-
ogy ward and electric medical record.
He was 164.5 centimeters tall, 57 kilograms weighs and
1.619 m2 body surface area. For the therapy of aggressive
B cell lymphoma, 4 cycles of Rituximab and 6 cycles of
THP-COP regimen (cyclophosphamide 650 mg/m2, day
1+vincristine 14 mg/kg [max. 2.0 mg], day 1 + pirarubicin
50 mg/m2, day 1 + prednisolone 100 mg/ body, days 1-5)
was treated every 3 weeks. Complete remission was ob-
tained, but thereafter, the tumor was relapsed. The patient
was admitted to receive autologous stem cell transplanta-
tion after treatment with other chemotherapy regimen. The
patients received R-IMVP16/CBDCA regimen (rituximab
375 mg/m2, day 1 + methotrexate 30 mg/m2, days 4-6 +
ifosfamide 1,000 mg/m2, days 4-8 + etoposide 80 mg/m2,
days 4-6 + carboplatin 300 mg/m2, day 4 + methylpredni-
solone 1,000 mg/m2, days 4-6 + mesna 250 mg/m2 x3,
days 4-8) every 3 weeks for 2 cycles, and subsequent
R-MEAM regimen (rituximab 375 mg/m2, day 1 + rani-
mustine 300 mg/m2, day 3 + citarabine 200 mg/m2, days
4-7 + etoposide 200 mg/m2 days 4-7 + merphalan 300
mg/m2 day 8 + hydrocortisone 100mg/body, days 4-7)
every 3 weeks for one cycle.
The patients also received valproic acid (VPA: De-
pakene-R tablets 1,200 mg/day) for the therapy of pre-
existing symptomatic epilepsia, thus therapeutic moni-
toring of (TDM) VPA was regularly conducted. More-
over, itraconazole (ITZ, Itrizole capsle 200 mg × 2) was
prescribed for the therapy of fungal infection.
3. Results
Before chemotherapy, plasma trough concentration of
VPA was maintained within a range of therapeutic
concentration. However, the VPA concentration de-
creased dramatically after receiving the chemotherapy,
in which the concentration (28.2 g/ml) was below the
minimal therapeutic concentration (40 g/ml) at day 8
(Figure 1). Unfortunately, an epileptic episode was
elicited during the collection of blood for the TDM of
VPA. The plasma VPA level gradually increased after
day 8 and the level was within the therapeutic range at
day 16. The second R-IMVP16/CBDCA regimen was
carried out thereafter. Similar pronounced decrease in
plasma VPA concentration was observed. The maximal
reduction was observed at day 7 (27.5 g/ml). The
concentration of VPA gradually increased after the end
of the chemotherapy regimen, and the concentration
was almost recovered at day 14. Due to the decrease in
platelet count, platelet transfusion was performed. Un-
fortunately, convulsion was induced during platelet
transfusion. The symptoms were ameliorated by the
systemic administration of diazepam.
Before treatment with the third chemotherapy regi-
men such as R-MEAM, Rikkunshi-to (Tsumura Rik-
kunshi-to extract granules, 7.5 g/day) was administered
for 14 days starting from the beginning of the chemo-
therapy to prevent the chemotherapy-induced decrease
in plasma VPA concentration. The plasma VPA con-
centration decreased, though to much lesser extent as
those observed in the preceding two chemotherapies, in
which the minimal concentration (38.7 g/ml) was near
the border of the therap eutic concentr ation. No episodes
of epilepsy were observed. Then, the patient success-
fully received autologous peripheral blood stem cell
transplantation.
10 20 30 40 50 60
0
20
40
60
80
100
120 Therapeutic concentration range
Chemotherapy 1Chemotherapy 2Chemotherapy 1
Rikkunshi-to (7.5g/day)
Plasma VP A conc entr ation (g/ml)
Days
Fi gur e 1. Tim e cou rse of p las ma VP A co nce ntr ati ons in a pati ent wit h ma lig nant ly mph oma w ho received cancer chemother-
apy; 1. rituximab/methotrexate/ifosphamide/carboplatin (R-IMVP16/CBDCA regimen); chemotherapy; 2. rituximab/ranimus-
ine/citarabine/etoposide/merphalan (R-MEAM regimen). t

M. ISHIHARA ET AL.
60
4. Discussions
We reported here a case of the reduction in plasma VPA
concentration after high-dose chemotherapy such as R-
IMVP16/CBDCA regimen and R-MEAM regimen. A
number of literatures have reported the metabolic inter-
actions between VAP and a variety of drugs, in which
carbapenem antibiotics are the representative agents that
cause a reduction in plasma VPA concentration [14,15].
Carbapenems facilitate glucuronidation of VPA [7], in-
hibit the transporter Mrp4 that mediates the efflux of
VPA from erythrocytes to plasma [6,8], and suppress the
intestinal transporter for VPA absorption [5]. On the
other hand, there have been only a few reports on the
pharmacokinetic interactions between anticancer drugs
and VPA. Ikeda et al. [13] reported in patients with tes-
ticular tumor who undertook the combination chemo-
therapy such as BEP regimen (bleomycin, etoposide, and
cisplatin) or TIP regimen (paclitaxel, ifosfamide, and
cisplatin) that a severe reduction in plasma VPA concen-
tration occur with th e concomitant seizures.
Although the precise mechanisms underlying the de-
crease in plasma VPA concentration induced by the can-
cer chemotherapy, several possibilities can be raised: 1)
facilitation of VPA glucuronidation are unclear, 2) inhi-
bition of transporters that mediates the efflux of VPA
from erythrocytes to plasma, 3) alteration of body fluid
volume by transfusion, 4) decrease in the absorption of
VPA from intestinal tracts.
In the present case, it is unlikely that the glucuronida-
tion of VPA was enhanced by the cancer chemotherapy,
since plasma concentrations of ITZ, which is metabo-
lized by hepatic cytochrome P450 enzyme 3A4 [16], and
its major metabolite OH-ITZ were also found to be low-
ered by R-IMVP16/CBDCA regimen, in which the con-
centrations of ITZ and OH-ITZ were 1,330 g/ml and
1,288 g/ml, respectively, before chemotherapy, while
the values were 405 g/ml and 372 g/ml, respectively,
at 7 days after the chemotherapy. Moreover, the possibil-
ity of inhibition of transporters that mediates the efflux
of VPA from erythrocytes to plasma, as mentioned above,
may be excluded.
The distribution volume of VPA is considered to be
12.5 l under food-deprived condition. Urine volume was
maintained cons tant in the present patient. Moreover, the
no changes in body weight was observed after the esca-
lating dose of infusion, indicating no marked changes in
fluid volume in this patient. Therefore, a possibility of
the alteration of body fluid volume by transfusion, as
mentioned above can be ruled out.
The chemotherapy agent that was used in common
with both chemotherapy regimens was only etoposide.
Etoposide causes dose-dependently myelosuppression,
alopecia, stomatitis and d iarrhea [17]. Etoposide-induced
diarrhea results from the disintegration of the epithelial
cells in lower intestinal tracts. Therefore, it is assumed
that the reduction of the absorption of VPA from the
intestinal tract due to the inciden ce of the injury of intes-
tinal epithelial cells contributes at least in part to the de-
crease in plasma VPA concentration, although no diar-
rhea or dysfunction of the upper intestinal tract such as
vomiting appeared in the present patient.
Based on the assumption that cancer chemotherapy
may cause an injury of intestinal epithelial cells, which
reduces plasma VPA concentration by the inhibition of
the absorption of orally administered VPA, any agents
that improve the intestinal dysfunction can be useful for
prevention of chemotherapy-induced decline in plasma
VPA concentration.
Rikkunshi-to is a kampo preparation that contains
Atractylodis Lanceae Rhizoma Pulveratum, Poria, Gin-
seng Radix, Pinelliae Tuber, Aurantii Nobilis Pericar-
pium, Zizyphii Fructus, Zingiberis Rhizoma, and Gly-
cyrrhizae Radix. This herbal medicine is used to alleviate
gastritis, dyspepsia, appetite poor, nausea and vomiting.
Takeda et al. [18] have shown in rats that hesperidin and
iso-liquiritigenin, both of which are ingredients of Rik-
kunshi-to, reverse cisplatin-induced decrease in food intake
by antagonizing cisplatin-induced decrease in plasma
acylated-ghrelin concentration through blockade of 5-
HT2B and 5-HT2C receptors.
In the present report, the chemotherapy-induced de-
crease in plasma VPA concentration was not marked and
no seizure episodes were observed, when Rikkunshi-to
was administered during and after cancer chemotherapy.
Therefore, Rikkunshi-to may be useful to attenuate the
malabsorption caused by cancer chemotherapy, although
we could not rule out a possibility that R-MEAM regi-
men itself produced less marked decrease in the absorp-
tion of orally administered drugs than R-IMVP16/CBDCA
regimen.
In conclusion, marked decrease in plasma VPA concen-
tration appeared in a patient with diffuse large B-cell lym-
phoma who received high-dose cancer chemotherapy.
However, no marked decrease in plasma VPA concentra-
tion was observed after chemotherapy, when Rikkunshi- to
was administered before, during and after chemotherapy.
Therefore, this herbal medicine may be useful to alle-
viate the decline in plasma VPA concentration in patients
receiving high-dose chemotherapy.
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