Pharmacology & Pharmacy, 2013, 4, 4-14
http://dx.doi.org/10.4236/pp.2013.47A1002 Published Online October 2013 (http://www.scirp.org/journal/pp)
Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin,
a Major Monoterpene Glucoside from the Root of Paeonia
lactiflora
Orleans N. K. Martey1,2, Xiaoyan Shi1, Xin He1,3*
1School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; 2Centre for Scientific Re-
search into Plant Medicine, Akwapim-Mampong, Ghana; 3Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin,
China.
Received July 27th, 2013; revised August 29th, 2013; accepted September 15th, 2013
Copyright © 2013 Orleans N. K. Martey et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Paeoniflorin (PF) is one of the main bioactive components of total glucosides of paeony (TGP) extracted from the root
of Paeonia lactiflora Pall. TGP exhibit various biological activities such as improvement in memory, hepatoprotection,
antimutagenic properties and platelet aggregation inhibition. The aim of this paper is to review the pharmacokinetics
(PK) of PF as a pure compound and in single or multiple herb(s) of traditional Chinese medicine (TCM) prescriptions.
The distribution of PF or PF in TCM fitted one or two compartmental model after oral administration or intravenous
injection, respectively. However, PF has a low bioavailability (BA) in rabbit (7.24%) and rat (3.24%) after oral admini-
stration. The PK profiles and BA of PF were remarkably improved when co-administered with sinomenine or glycyr-
rhizin acid. The PK profiles and BA of PF in Radix Paeonia Rubra (RP-R) and Jing-zhi guan-xin were improved, but in
co-administration of RP-R with Radix Angelicae Sinensis, the BA was significantly reduced. PK profiles and BA of PF
in Shan yao gan-cao tang or Danggui-Shaoyao-San was either remarkably improved or not. However, neither the PK
profiles nor the BA of PF in Radix paeonia alba, Huangqin-tang Si ni san or Tang-Min-Ling-Wan was improved. Me-
tabolism in the liver did not play any role in the low oral BA of PF. The low BA was thus attributed to poor permeation
due to low lipophilicity, P-glycoprotein mediated efflux, intestinal bacteria and hydrolytic degradation in the intestine
by the intestinal brush border lactase phlorizin hydrolase (LPH) and certain esterases. These findings show the in vivo
course of PF and provide information on the maximum biological actions of PF that may help traditional Chinese herbal
medicinal practitioners.
Keywords: Bioavailability; Intestinal Bacteria; Pharmacokinetics; Paeoniflorin (PF); P-glycoprotein (P-gp)
1. Introduction
Paeonia lactiflora Pall is a Chinese herb commonly
known as Baishao or white peony (Figure 1) from the
Ranunculaceae family. According to traditional Chinese
medicine (TCM), P. lactiflora functions either as a single
herb or in combination for nourishing blood and Yin,
calming the liver to relieve pain and suppressing hyper-
active liver-Yang. P. lactiflora is used as an analgesic,
anti-inflammatory and antispasmodic drug in the treat-
ment of amenorrhea, dysmenorrhea, and pain in the chest
and abdomen. Radix Paeoniae is also used to treat de-
mentia, headache, vertigo, spasm of the calf muscles,
liver disease, and allergies, and as an anticoagulant [1-4].
Chemical compounds isolated from P. latiflora include
pentagalloylglucose, paeonilactones A, B and C, paeonol,
benzoic acid, trihydroxybenzoic acid, gallic acid and mo-
noterpene glucosides such as paeoniflorin, oxypaeoniflo-
rin, isobenzoylpeoniflorin, 4’-O-methyl-paeoniflorin, iso-
paeoniflorin, isobenzoylpeoniflorin 3’-O-galloyl-paeoni-
floin, 4’-O-galloypaeoniflorin, albiflorin, 4’-O-galloylal-
biflorin, 6’-O-beta-D-glucopyranosylalbiflorin, and 6’-O-
benzoylalbiflorin [5-9].
Paeoniflorin (PF) (Figure 2(a)), the major bioactive
monoterpene glucoside from P. lactiflora is characterised
as a neutral compound (MW 428.47) with good solubility
(log P = 2.88) indicating low lipophilicity (http://www.
chemnetbase.com). Pharmacological studies have indi-
cated that PF has anti-inflammatory [10], anti-coagulant
*Corresponding author.

Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the
Root of Paeonia lactiflora
5
(a) (b)
Figure 1. Picture of a P. lactiflora plant (a) and dried roots
(b).
Figure 2. Proposed metabolic pathways of paeoniflorin in
the intestine and structures of other compounds that play a
role in its pharmacokinetics.
[11], neuromuscular blocking [12], cognition-enhancing
[13-15], anti-hyperglycemic [16] and neuroprotective [17,
18] effects. Knowledge of bioactive constituents of me-
dicinal herbs with favorable pharmacokinetic properties
is essential for understanding the relationship between
consumption and pharmacological effects with the view
of identifying therapeutic principles in herbal medicines.
Different from single compound of Western drug, TCM
is a complex system consisting of multiple compounds.
Pharmacokinetic studies are valuable in evaluating the
rationality and compatibility of herbs and prescription
due to the complexity of chemical compounds present.
Normally, one major active ingredient is selected as the
indicative compound and the interactions of ingredients
in the herb or prescription are clarified based on the
pharmacokinetic behaviour of the selected compound.
Hence, the development of pharmacokinetic study on PF,
the major bioactive monoterpene glucoside of P. lacti-
flora, as a pure compound and in single or multiple
herb(s) of TCM Prescriptions was reviewed in this paper.
2. Pharmacokinetics and Poor Oral
Bioavailability of PF as a Pure Compound
2.1. Pharmacokinetics of PF as a Pure
Compound
The pharmacokinetics of PF as a pure compound has
been studied in different species and different routes of
administration. The plasma concentration-time curve for
dog, rabbit and rat in different papers showed species-
independency after intravenous injection [19-23] (Table
1). The logarithmic plasma concentration-time curve of
PF (30 mg/kg) in rats after intravenous injection showed
a rapid decline initially but then slowed eventually
(Wang et al. 2008), thus resulting in a biphasic curve
characterized by C = C1e−λ1t + C2e−λ2t, that is, the sum of
two exponential terms C1e−λ1t and C2e−λ2t, where C1 and
C2 refer to the plasma drug concentration given by the
corresponding zero-time intercept, and λ is the rate con-
stant with an associated half-life, t. This distribution
could therefore be fitted into a two-compartment model
as distribution equilibrium is reached between plasma
and highly perfused tissues with further redistri-bution
from well-perfused tissues to less-perfused tissues during
Table 1. Pharmacokinetic parameters of the intravenous
injection of pure paeoniflorin in rabbits, dogs and rats at
different doses.
Parameter (s) Rabbit
(n = 5)
Dog
(n = 3)
Rat
(n = 8)
Dose (mg/kg) 25.00 11.25 30.00
t1/2α (min) 5.93 ± 2.69 6.30 ± 1.80 32.4 ± 16.8
t1/2β (min) 66.02 ± 27.63133.4 ± 84.9 280.2 ± 108.6
K21 (1/min)a 0.052 ± 0.0310.019 ± 0.007 0.0025 ± 0.0016
K10 (1/min)b 0.035 ± 0.0060.004 ± 0.008 0.019 ± 0.008
K12 (1/min)c 0.069 ± 0.0360.066 ± 0.024 0.0051 ± 0.0092
VC (mL/kg) 165.4 ± 59.784.5 ± 13.6 -
VB (mL/kg) 516.8 ± 0.32539.2 ± 104.2 450 ± 250
CL (mL/min/kg)6.11 ± 3.29 3.40 ± 1.00 7.66 ± 0.23
Values represent: mean ± SD; aK21: Transfer rate constant from the pe-
ripheral compartment (2) to the central compartment (1); bK10: Elimination
rate constant from the central compartment. cK12: Transfer rate constant
from the central compartment (1) to the peripheral compartment (2).

Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the
Root of Paeonia lactiflora
6
subsequent decline. However, a logarithmic plasma con-
centration-time curve of PF (300 mg/kg) after oral ad-
ministration in rats showed fast absorption with a termi-
nal linear decline of plasma concentration characterised
by the monoexponential equation C = C(0)e−λt. This dis-
tribution could therefore be fitted into a one-compart-
mental model as equilibrium is rapidly reached between
plasma and highly perfused tissues [22].
PF have a low bioavailability of about (7.24 ± 4.15)%
after 250 mg/kg intragastric (ig) dose in rabbits [19], and
about (3.12 ± 0.76)% after oral administration in rats
[21-23]. Takeda et al. [24] showed that the cumulative
urinary and fecal excretions of PF at 5 mg/kg dose after
intravenous injection were 50.5% and 0.22% of the dose
within 7 h, 1.0% and 0.08% of the dose after oral ad-
ministration within 48 h, respectively. The cumulative
bile excretion after intravenous or oral administration in
rats at a dose of 0.5 mg/kg were 6.9% and 1.3% of the
doses within 24 h, respectively. The total renal and bile
clearance was less than the total clearance value. This
conforms to the findings of Chen et al. [20] who found
out that after the ig administration of 550 mg/kg of PF,
10% and 1% of PF were removed from rat feces and
urine, respectively, and that 8.64% could be recovered
from the rat bile within 7 h after 55 mg/kg intravenous
administration. PF was also rapidly removed from the
blood by the kidney to 36.85% in 20 min and 79.33% in
7h of the accumulated recovery amount of excretion after
11.25 mg/kg total intravenous doses administered to dogs.
An accumulated amount of only 3.77% within 7 h was
also found in the bile after intravenous administration
[19]. These results may be due to poor absorption from
the gastrointestinal tract, decomposition in the intestine
by bacterial microflora, and/or first-pass elimination in
the gut wall or liver.
2.2. Poor Oral Bioavailability of PF in Vivo
PF as a single compound has a wide range of pharma-
cological actions but low bioavailability. In an in vivo
assessment to estimate the first pass elimination by intes-
tinal flora, the extraction ratios of PF in the gut wall,
liver and lungs were assessed by comparing the AUCs
after various routes of administration [21]. The plasma
concentration profile of PF after intraportal administra-
tion [(0.5 and 5) mg/kg] was close to that of intravenous
administration. The mean pulmonary extraction ratio
from the veins and the arteries was also estimated to be
0.06. These findings suggest that PF has a negligible he-
patic extraction ratio and that it is not metabolized in
liver and lungs. Rather, the unbound fraction is degraded
by intestinal flora (Bacteroides fragilis or Lactobacillus
brevis) to form the 7S and 7R isomers of paeonime-
taboline I as major metabolites, along with the 7R and 7S
isomers of paeonimetaboline II as minor metabolites
[25,26] (Figure 2).
Liu et al. studied the action of lactase phlorizin hy-
drolase (LPH, a brush border membrane-associated en-
zyme in intestinal cells that hydrolyse lactose) to PF us-
ing a single-pass four site rat intestinal perfusion model.
There was significant decrease of PF to paeoniflorigenin
(>80%) in the perfusate in the presence of LPH inhibitor,
gluconolactone, with a lower apparent absorption in the
upper small intestine. In this region, LPH is more active
and esterases catalyse the hydrolysis of PF to form ben-
zoic acid [27] (Figure 2).
3. Pharmacokinetics of PF in TCM
Prescriptions
3.1. Pharmacokinetics of PF in a Single-Herb
Prescription
Radix paeonia rubra (RP-R) and radix paeonia alba
(RP-A) are two independent traditional Chinese herbal
medicines, both of which are obtained from the root of P.
lactiflora Pall. (Figure 1(b)) and have different pharma-
cological actions. The former is obtained directly from
the dried roots of P. lactiflora Palls. grown wild, while
the latter is from a decoction of the dried peeled roots of
P. lactiflora Pall. grown domestically. RP-R reportedly
exhibits pharmacological actions against coronary dis-
eases (e.g., angina pectoris, chronic-cardiac ischemia, ven-
tricular tachycardia, augmenting blood of coronary artery,
anti-acute myocardial ischemia); it also features anti-
platelet aggregation, anti-thrombogenesis, activation of
fibrinolysis, antihyperlipidaemic effect, improvements in
blood hypervisicosity syndrome and decreased blood pres-
sure, anti-atherosclerosis, heart or liver protection, anti-
tumor effects, and protection of neurons against kainic
acid-induced neurotoxicity [28,29]. RP-A has been re-
ported to exhibit anti-inflammatory, anti-viral, spasmo-
lytic, analgesic and liver protection effects [30,31].
The pharmacokinetic differences of PF have been in-
vestigated in RP-R and RP-A with respect to its low
bioavailability following oral administration in aqueous
PF solution, decoction of RP-R and RP-A at doses of 300
mg/kg PF content by oral gavages in rats using a simple
high-performance liquid chromatography (HPLC) me-
thod [22]. The oral absorption kinetics of PF in RP-R and
RP-A were influenced when compared to PF alone fol-
lowing oral administration (Table 2). The absorption
half-life of PF in RP-R was much delayed followed by
PF in RP-A and then by PF alone. The peak time (tmax)
occurred much longer in RP-R followed by RP-A and
then by PF alone. This findings indicates that there was a
delay in the absorption of PF until it reaches the value at
which point the rate of elimination matches the rate of

Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the
Root of Paeonia lactiflora
7
Table 2. Pharmacokinetic parameters of PF in rats after
oral administration of PF solution, RP-R and RP-A aqueous
extracts at a dose containing 300 mg/kg of PF using a simple
HPLC method.
Parameters Paeoniflorin Radix
Paeoniae ubra
Radix
Paeoniae alba
Ke (1/h) 0.19 ± 0.09 0.20 ± 0.03** 0.12 ± 0.04
Ka (1/h) 8.73 ± 5.53 1.55 ± 0.79*• 5.10 ± 3.43•
t1/2α (h) 0.11 ± 0.07 0.54 ± 0.20**•• 0.16 ± 0.09•
t1/2β (h) 4.27 ± 1.57 3.58 ± 0.61* 6.19 ± 2.06
tmax (h) 0.58 ± 0.34 1.67 ± 0.43**•• 0.80 ± 0.35•
Cmax (µg/mL) 3.34 ± 1.18 3.69 ± 1.46* 1.46 ± 0.29•
AUC (µg·h/mL) 18.85 ± 7.54 24.89 ± 7.41** 10.61 ± 1.51•
CL (h·L/Kg) 15.10 ± 3.17 12.62 ± 3.48** 21.12 ± 7.52••
Vd (L/Kg) 90.56 ± 32.81 66.57 ± 26.80** 194.20 ± 46.33••
Frel (%) 100 132.1 56.3
Values represent: mean ± SD, oral administration of RP-R versus RP-A,*P <
0.05; **P < 0.01, oral administration of RP-R, RP-A versus paeoniflorin
solution: •P < 0.05; ••P < 0.01.
absorption at maximum concentrations of PF in RP-R,
RP-A and PF alone, respectively. However, the signifi-
cantly decreased Cmax of PF in RP-A with a correspond-
ing decrease in the area under the concentration-time
curve (AUC) of (10.61 ± 1.56) µg·h/mL showed that
even though there was a delay of absorption of PF in
RP-A, there was a decrease in bioavailability when
compared to PF in RP-R and PF alone, with AUC of
(24.89 ± 7.41) µg·h/mL and (18.87 ± 7.54) µg·h/mL,
respectively. These findings correspond to the remark-
able improvement in the relative bioavailability of PF
alone from 3.26% to 4.26% of PF in RP-R, but a re-
markable decrease to 1.82% in RP-A after oral admini-
stration to rats.
In a similar study using an HPLC-electrospray ioniza-
tion mass spectrometry, Feng et al. [32] investigated the
pharmacokinetic properties of PF following oral admini-
stration of aqueous extracts of RP-R and RP-A contain-
ing 0.2 g/g crude drug to rats. The results (Table 3)
showed a higher Cmax, higher AUC0-∞, an increased tmax, a
delayed t1/2, and a lower Ke of PF in RP-R than in RP-A
with Cmax, AUC0-∞, tmax, t1/2 and Ke at a significant dif-
ference P < 0.01. This also supports the fact there was
oral bioavailability increase of PF in RP-R than RP-A
due to the significant increase in AUC and Cmax with a
remarkable change in peak time.
Wu et al., (2008) also reported an AUC0-t [(4.6 ± 0.85)
mg·h/L], Cmax [(1.55 ± 0.53) mg/L] and MRT [(3.08 ±
0.76) h] of PF in RP-R. However, AUC0-t, Cmax, and
MRT of PF in RP-R were significantly changed, P <
0.05, to [(3.36 ± 0.56) mg·h/L; (0.9 ± 0.42) mg/L; (5.19 ±
1.95) h], respectively when RP-R was co-administrated
Table 3. Pharmacokinetic properties of PF following oral
administration of aqueous extract of RP-R and RP-A con-
taining 0.2 g/g crude drug to rats using an HPLC-ESI-MS.
Parameters Radix Paeoniae rubra Radix Paeoniae alba
t1/2 (h) 1.86 ± 0.27 0.85 ± 0.11
Ke (1/h) 0.35 ± 0.10 0.79 ± 0.29
tmax (h) 0.67 ± 0.07 0.33 ± 0.02
Cmax (ng/mL) 185.24 ± 26.24 34.44 ± 13.42
AUC0-t (ng·h/mL)48572.38 ± 480.18 288.66 ± 80.38
AUC0-∞ (ng·h/mL)52274.73 ± 489.32 315.08 ± 85.44
Values represent: mean ± SD.
with Radix Angelicae Sinensis to rats using HPLC-
MS/MS method [33]. RP-R in the presence of Radix
Angelicae Sinensis can significantly reduce the bioavai-
lability of PF in RP-R. The kinetic process of paeoniflo-
rin in plasma showed two compartment model after oral
administration of RP-A extract at doses of 0.2, 0.4, 0.8
g/kg to rats using an HPLC-MS/MS method [34].
The differences between the plasma concentration
profiles of PF in RP-R or RP-A compared to PF alone is
evidence of drug-drug interactions as a result of different
complex chemical compounds present in herbal medi-
cines. This could occur either by induction of metabolic
enzymes, P-glycoprotein, LPH, esterase’s, or degradation
by intestinal bacteria. It was reported by Feng et al. [32]
that except for PF, the other monoterpene glycosides of
albiflorin, benzoylpaeoniflorin and some acids of benzoic
acid, trihydroxybenzoic acid were the common compo-
nents existing in both drugs. Paeonol and paeoniflorin-
sulfite were characteristic chemical constituents for RP-R
and RP-A, respectively. The content of albiflorin and
oxypaeoniflorin in RP-A was larger than that in RP-R,
while the content of PF and benzoic acid was higher in
RP-R than that in RP-A. RP-R as a decoction may be
more useful clinically in TCM hospitals as evidenced by
the pharmacokinetic profiles above.
Patients are the final users of drugs and it will be in-
teresting if pharmacokinetics studies are considered in
animal models compared to normal animals. In a study,
Jiang et al. [35], investigated the pharmacokinetics of PF
in RP-R following intragastric administration of RP-R
powder (low dose: 7 g/kg or high dose: 14 g/kg contain-
ing 357 mg/kg or 714 mg/kg PF, respectively) to normal
rats (NR) and alpha-naphthylisothiocyanate induced acute
cholestasis hepatitis (ACH) rats using Ultra Performance
Liquid Chromatography (UPLC)-ESI-MS/MS method.
This showed remarkable improvement in absorption ki-
netics in both low dose (LD) and high dose (HD) admin-
istered with increased AUC0-t, increased AUC0-∞, high
tmax and reduced CLz/F in the ACH rats compared to that
of the normal rats with corresponding parameters shown

Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the
Root of Paeonia lactiflora
8
in Table 4. The induced cholestasis is characterized by
periportal bile duct epithelial degeneration and necrosis
and a pronounced neutrophil infiltration which results in
low levels of cytochrome P450 [36,37]. The increase in
plasma concentrations and decreased clearance of PF in
ACH rats compared to NR may be due to the disease
condition. Similar results were observed by He et al. [38]
on the effect of cerebral Ischemia-reperfusion (CIR) on
pharmacokinetic fate of paeoniflorin after intravenous
administration of Paeonia radix extract (at 60 mg/kg PF)
to rats using an HPLC method. The CIR significantly, P
< 0.05, increased, AUC [(9626.00 ± 1053.98) µg·min/
mL], decrease CL [(0.0071 ± 0.0013) mg/(kg·min)] and
prolong the half-life of distribution [t1/2α (2.04 ± 0.84)
min] and elimination [t1/2β (24.51 ± 9.23) min] compared
to normal rats with corresponding parameters as (5338.71
± 467.54) µg·min/mL, (0.0162 ± 0.0023) mg/(kg·min),
0.69 ± 0.19) min and (18.77 ± 3.74) min.
3.2. Pharmacokinetics of PF in Multiple-Herb
Prescription
The pharmacokinetics of PF in single-herb extracts had
been shown to be influenced by the complexity of other
phytochemicals that may be present. Most TCM pre-
scriptions are multiple herbal formulations. Thus, know-
ledge of the pharmacokinetics of marker compounds in
the presence of other herbs cannot be overemphasised
primarily due to its relevance to the biological actions or
otherwise of the herbal prescription. Shao-yao Gan-
caoTang (SGT), which is composed of Radix P. lacti-
flora and Radix Glycyhhizea uralensis, is one of the most
famous Chinese prescriptions. SGT is widely used in
China and Japan for acute abdominal pain and muscles
stiffness. The pharmacokinetics of PF following oral
administration of 2 mg/ml SGT extract (containing 10
mg/kg PF) to mouse using a simple and rapid HPLC
method was significantly improved compared to the ki-
netics data of PF after oral administration of Paeoniae
Radix extract alone [39]. The results and the previously
reported kinetic data of PF after oral administration of
Paeoniae Radix extract alone (Table 5), showed high tmax ,
increased Cmax, increased AUC0-t, decreased Vd/F, (Vd
means apparent volume of distribution, F means bioavai-
lability), reduced CL/F and prolonged t1/2, respectively.
Therefore the absorption kinetics and bioavailability sig-
nificantly, P < 0.01, improve since the Cmax and AUC
value increase with an increase in the peak time. This
therefore took longer for the amount of PF to reach the
value at which the rate-step limiting matches the rate of
absorption Cmax. This conclusion conforms with Shen et
al. [40] that, generally, the absorption of Shaoyao (Paeo-
niae Radix) components in SGT was increased when
Table 4. Pharmacokinetics of PF in RP-R following intra-
gastric administration of RP-R powder to normal (NR) and
alpha-naphthylisothiocyanate induced acute cholestasis he-
aptitis (ACH) rats.
Normal Rats ACH Rats
RP-R Powder (g/kg)
Parameters
7 14 7 14
AUC0-t
(mg·h/L) 8.14 ± 0.6216.58 ± 0.92 15.62 ± 3.1 31.71 ± 3.00
AUC0-∞
(mg·h/L) 9.64 ± 1.1220.5 ± 0.61 17.27 ± 4.59 34.87 ± 4.03
tmax (h) 0.08 ± 0.000.44 ± 0.21 0.38 ± 0.16 0.58 ± 0.20
CLz/F
(L/h/kg) 37.40 ± 4.1834.78 ± 1.05 21.59 ± 4.59 20.69 ± 2.41
Values represent: mean ± SD.
looking at the pharmacokinetics of characteristic effec-
tive ingredients from individual and combination Shao-
yao and Gancao (Glycyrrhizae Radix) treatment in rats
using HPLC fingerprinting. In contrast, Gan et al. [41]
reported low bioavailability of PF in SGT compared to
PF in Radix Paeonea decoction following oral admini-
stration of 60 g/kg SGT and 30 g/kg Radix paeonea de-
coction (165.7 mg/kg and 182.27 mg/kg PF) to rats using
an UPLC method. The results showed decrease in AUC0-t
[(2903 ± 92 vs 3846 ± 477) µg·h/L], AUC(0-∞) [(2736 ±
164 vs 4046 ± 514) µg·h/L], AUC0-t/dose [(15.78 ± 0.84 vs
21.05 ± 2.61) µg·h/L/(mg/kg)], and AUC(0-∞)/dose [(16.51
± 0.99 vs 22.14 ± 2.81) µg·h/L/(mg/kg)] and high CL/F
[(60.8 ± 3.7 vs 45.9 ± 7.1) L/h/kg] of PF in SGT and
radix paeonea decoction, respectively.
The pharmacokinetic parameters (Table 5) of PF of
Jing-Zhi-Guan-Xin (JZGX), composed of Radix Salviae
Miltiorrhizae, Radix Paeoniae Rubrae, Rhizoma Chuan-
xiong, Flos Carthami, and Lignum Dalbergiae Odoraf-
era, were remarkably improved when compared with that
of Paeoniae Radix extract alone (longer tmax, increased
Cmax; increased AUC0-∞, longer MRT and a longer t1/2)
after oral administration, indicating that the absorption of
PF after the oral administration of JZGX tablets was sig-
nificantly greater than that of Paeoniae Radix extract
alone and that it occurred with a significant increase in
AUC after oral administration of JZGX tablets. These
findings suggest that relatively more PF was absorbed
[42].
Danggui-Shaoyao-San (DSS), composed of Radix
Angelica sinesis, Radix P. lactiflora, Sclerotium poriae
Cocos, Rhizoma Atractylodis macrocephalae, Rhizoma
Alisma orientalis and Radix Linguistici wlichii, is clini-
cally used for the treatment of vascular dementia (VD).
The pharmacokinetics of PF (Table 6), either in pure
form (224 mg/kg) or in DSS (3.54 g/kg containing 224
mg/kg PF) following oral administration to VD rats

Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the
Root of Paeonia lactiflora
9
Table 5. Pharmacokinetics parameters of PF following oral administration of SGT and JZGH to mouse and beagle dogs re-
spectively compared to kinetic data of Radix poeny extracts (RPE).
Parameters RPE SGT JZGH
tmax (min) 14.0 ± 4.18 17.0 ± 4.47 130.00 ± 30.98*
Cmax (ng/mL) 86.34 ± 18.67 111.56 ± 20.83* 210.49 ± 23.89*
AUC0-t (ng·min/mL) 8126.97 ± 2004.62 12293 ± 1945.96* -
AUC0-∞ (ng·min/mL) 9746.10 ± 2554.62 16335 ± 3641.46* 43066.50 ± 10119.51*
t1/2 (min) 94.00 ± 12.35 116.17 ± 35.02 147.52 ± 28.98*
CL/F (mL/min/kg) 1113.35 ± 420.63 644.74 ± 84.45* -
Vd/F (L/kg) 147.44 ± 40.78 103.05 ± 20.45* -
MRT (min) 135.64 ± 18.51 109.64 ± 50.12 212.87 ± 41.82*
Values represent: mean ± SD; compared with RPE *P < 0.05; **P < 0.01; SGT: Shao-yao Gan-cao Tang; JZGH: Jing-Zhi-Guan-Xin.
Table 6. Pharmacokinetics of PF, either in pure form or in
DSS following oral administration to normal and vascular
dementia rats.
Normal Rats Vascular Dementia Rats
Parameters PF PF-DSS PF PF-DSS
t1/2 (h) 5.95 ± 1.53 6.94 ± 1.22 11.97 ± 1.22 9.64 ± 2.61
MRT (h) 5.25 ± 1.05 8.16 ± 1.88 10.47 ± 1.30 10.58 ± 3.83
AUC (µg·h/mL) 7.89 ± 1.73 5.64 ± 0.71 11.95 ± 1.75 8.92 ± 0.99
Values represent: mean ± SD; PF: Paeoniflorin; DSS: Danggui-Shaoyao-San.
showed significant delay in absorption half life, pro-
longed mean resident time and an increase AUC com-
pared to normal rats with t1/2 and AUC. These observa-
tions shows that the bioavailability of PF in DSS in VD
was improved compared to PF in DSS and PF alone in
NR [43]. Liu et al. also reported that the Cmax of PF in
DSS [(143 ± 65) ng/mL] was significantly lower than PF
alone [(659 ± 147) ng/mL], with a corresponding AUC
of PF in DSS [(242 ± 126) ng·h/mL] significantly lower
than PF alone [(722 ± 158) ng·h/mL]. While a significant
higher Cmax [2132 ± 560 ng/mL.] with a remarkable in-
crease AUC of PF in RP-A [2259 ± 910 ng·h/mL] after
oral administration to rats (calculated at a normalized
dose of 20 mg/kg PF) using liquid chromatography-tan-
dem mass spectrometry method. The contradiction of
bioavailability of PF in SGT and DSS may be attributed
to poor standardization from sourcing of raw material to
final product. This may therefore contribute to differ-
ences in chemical composition and drug-drug interac-
tions.
Huangqin-Tang, a compound prescription consisting
of four medicinal herbs (i.e., Radix Scutellariae bai-
calensis, Radix P. lactiflora, Radix G. uralensis and
Ziziphus jujuba Mill.) showed no significant difference
in the pharmacokinetic parameters of PF in compound
prescription compared with the single herb extract of P.
lactifola (Ta b le 7 ) after oral administration containing 10
mg/kg PF content using a simple validated HPLC
method [26]. Similarly, the results of a study (Table 8)
Table 7. Pharmacokinetics parameters of PF in Huangqin-
Tang and P. lactiflora.
Parameters Paeonia lactiflora Huangqin-Tang
t1/2α (h) 0.16 ± 0.00 0.27 ± 0.08
t1/2β (h) 2.17 ± 0.35 2.46 ± 1.01
tmax (h) 0.65 ± 0.28 0.97 ± 0.06
Cmax (ng/mL) 1626.75 ± 541.09 1485.65 ± 652.21
AUC0-∞ (ng·h/mL)24729.91 ± 1630.99 6273.19 ± 2140.36
MRT (h) 14.78 ± 8.31 18.04 ± 5.64
Values represent: mean ± SD.
Table 8. Pharmacokinetics parameters of PF following oral
administration of paeoniflorin solution and Si Ni San ex-
tracts to rats.
Parameters PF Si Ni San
t1/2α (min) 3.42 ± 1.57 18.25 ± 17.30
t1/2β (min) 518.42 ± 132.22 381.82 ± 91.35
tmax (min) 22.31 ± 8.28 34.38 ± 26.78
Cmax (ng/L) 640.18 ± 125.86 250.45 ± 36.17
Values represent: mean ± SD.
conducted by Liu et al. [17] on the pharmacokinetics of
PF between pure PF and Si Ni San, a TCM formulation
composed of Radix Bupleurum falcatum L., Fructus im-
maqturus, Radix P. lactiflora, and Radix G. uralensis
following oral administration were comparable. The
pharmacokinetic parameters for PF in Si Ni San and PF
alone were Cmax (250.45 ± 36.17) µg/L, tma x (34.38 ±
26.78) min; and Cmax (640.18 ± 125.86) µg/L, tma x (22.31
± 8.28) min, respectively. The low bioavailability of PF
in Si Ni San indicates that instead of PF responsible for
the pharma cological effects, possibly its metabolites by
intestinal bacteria and liver promoted by other compo-
nents in Si Ni San [44].
Tang-Min-Ling-Wan (TMLW), another prescription of
TCM containing Radix Scutellariae, Radix Paeoniae
Alba, Rhizoma Coptidis, Radix et Rhizoma Rhei, Fructus

Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the
Root of Paeonia lactiflora
10
Aurantii Immaturus, Radix Bupleuri, Rhizoma Pinelliae,
is used for hyperlipidemia and hyperglycemia and in-
creasing insulin expression and antioxidant enzyme ac-
tivity. It is used clinically in the treatment of type 2 dia-
betes mellitus and diabetic complications [45]. An
HPLC-MS/MS method was developed and applied to
pharmacokinetics of PF after oral administration of 55
mg/kg PF content of TWLW (11.0 g/kg) and RP-A ex-
tract (0.63 g/kg extract) by Tong et al. The peak concen-
tration of PF in TWLW occurred more rapidly [tmax =
(0.28 ± 0.09) h] but with a higher plasma concentration
[Cmax = (1591 ± 416.9) ng/mL] whiles the peak concen-
tration of PF in RP-A extract occurred slowly [tma x =
(0.89 ± 0.27) h] but with a lower plasma concentration
[Cmax = (301.3 ± 96.81) ng/mL] However there was no
significant differences of PF bioavailability between
TWLW [t1/2 = (2.17 ± 0.76) h; AUC0-t = (1443 ± 207.5)
ng·h/mL.] and RP-A extract [t1/2 = (1.97 ± 0.63) h;
AUC0-t = (1495 ± 521.2) ng·h/mL]. Salmul-tan is an
herbal medicine prescribed in South Korea. It is also
known as Si-Wu-Tang or Shimotsu-to, prescribe in
China and Japan, respectively. It is used traditionally for
palpitation, amenorrhea, fatigue, dizziness. Salmul-tan or
Si-Wu-Tang or Shimotsu-to is composed of Angelica
gigas, Cnidium officinale, Paeonia lactiflora and Reh-
mannia glutinosa. Hwang et al. [46] investigated whether
food and gender could influence the pharmacokinetic
profile of PF following a single oral dose (80 mg/kg) of
Si-Wu-Tang to rats using an HPLC method. The results
showed no significant difference by gender difference.
However, food intake significantly, P < 0.05, increased
the availability [(F(rel) = 2.21)] and extent of absorption
of PF compared to fast state with increased Cmax [(1.10 ±
0.35 vs 0.47 ± 0.29) µg/mL] and AUC0-∞[ (3.12 ± 1.61)
vs (1.41 ± 0.89) µg·h/mL], respectively.
Buyang Huanwu decoction (BYHWD) is a Chinese
traditional compound. BYHWD is composed of Radix
Astragalus membranaceus, Radix Angelicae Sinensis,
Radix P. lactiflora Pall.; Radix Ligustici wallichii, Car-
thamus tinctorius L, Amygdalus persica L.; and Phere-
tima aspergillum. It has been developed as a drug to treat
stroke-induced disabilities and has proven effective in
treating cerebrovascular illnesses [47]. A reversed phase-
HPLC method developed and applied in a pharmacoki-
netic studies of PF after intravenous administration of
BYHWD and total glycosides to rats fitted a two com-
partmental model while an oral administration to rats by
Zhang et al. [48] fitted a one compartmental model with
first order absorption. Wuji Pill is a prescription of a tra-
ditional Chinese medicine commonly used to treat gas-
tro-intestinal disorder. It consists of three herbs such as
Rhizoma Coptidis, Fructus Evodiae Rutaecarpae and
Radix Paeoniae Alba. A pharmacokinetic study after oral
administration of Wuji Pill to rats using a developed
LC-MS/MS method by Yuan et al. [49] to simultane-
ously determine six alkaloids [palmatine, jatrorrhizine,
berberine coptisine (from Rhizoma Coptidis); Evodia-
mine, rutacarpine (from Fructus Evodiae Rutaecarpae)]
and one monoterpene glycoside [paeoniflorin, (from
Radix Paeoniae Alba)] showed that PF of Radix Paeo-
niae Alba fitted a two compartmental model. This is
comparable to the result of an intravenous administration
of PF alone reported by Wang et al. [22]. However, other
compound prescriptions discussed in this review fits one
compartmental model. This shows that the use of multi-
ple herbs in a prescription can alter the pharmacokinetic
status as well as its pharmacological effects.
4. Influence Factors on PF Absorption
4.1. Using the Everted Rat Gut Sac Model
The everted rat gut sac model [50] has also been used to
establish that PF is not metabolised in the intestine. This
showed a total recovery rate (in the serosal side, mucosal
side and gut side tissue) higher than 97% and an uptake
in the sac tissue about 10% with a saturation of PF ab-
sorption in to the sac content at 80 µM [51]. The possi-
bility that an energy-dependent carrier-mediated trans-
port may be involved in the PF intestinal absorption has
been speculated, since in vivo studies with an unrestricted
conscious rat demonstrated that with co-administration
with sinomenine (90 mg/kg), the peak plasma concentra-
tion of PF in rats was elevated, the peak time delayed,
AUC0-t increased with prolonged MRT, clearance de-
creased and volume of distribution declined [52]. A simi-
lar outcome was reported upon co-administration of PF
and glycyrrhizin acid [53] (Figure 2).
In the everted rat gut system the fraction of PF in the
sac content was nearly elevated to 1.5-fold and 2.5-fold,
respectively, when the gut sac was treated with 16 µM
and 136 µM sinomenine in TC 199 medium for 45 min
of incubation. Similarly, treatment of the gut sac with
100 µM verapamil and 1.3 mM quinidine significantly
increased PF absorption in the sac content to 2.1-fold and
1.5-fold, respectively. These elevated levels of absorp-
tion of PF in the presence of inhibitors were consistent
with that of digoxin (113 µM) a P-glycoprotein substrate,
which was increasingly absorbed to about 2.5-fold when
co-incubated with sinomenine (136 µM) relative to the
non-sinomenine treated gut sac [51]. Studies on the effect
of glycyrrhizin on the intestinal absorption of PF by the
everted rat sac model also showed that PF could be ab-
sorbed in the duodenum, jejunum, ileum and colon of
rats and glycyrrhizin can improve the efflux of PF from
intestinal cells. These findings from the everted rat gut
system therefore suggest that PF is not metabolised in the

Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the
Root of Paeonia lactiflora
11
intestine and that its low bioavailability may be due to
P-gp mediated efflux, a hypothesis that was partly in
conformity with the findings of Liu et al. [27] who in-
vestigated the mechanism for the poor oral bioavailabil-
ity of PF and the role of intestinal disposition and inter-
action with sinomenine using a single-pass four site rat
intestinal perfusion model and a cultured Caco-2 cell
model.
4.2. Using the Rat Perfusion and Caco-2 Cells
Models
In both model systems, absorption of PF was shown to be
very poor. In the Caco-2 cell model, the apparent per-
meability from the apical to the basolateral was 0.48 ×
10−6 cm/s. This value is similar to poorly absorbed com-
pounds such as mannitol at 1.7 × 10−6 cm/s and sulfasa-
lazine at 0.34 × 10−6 cm/s and is 23 times lower than
propranolol at 11.3 × 10−6 cm/s, a highly absorbed com-
pound [54,55]. The rat intestinal perfusion model also
showed a similar results with < 0.4 in all four intes-
tines lower than propranolol ( > 3.5) but similar to
rutin ( < 0.58) and mannitol with < 0.3 [56].
Furthermore, in the perfusate model predominant intes-
tinal metabolites of PF such as paeoniflorigenin and
benzoic acid were found. The presence of the metabolites
were not affected in the presence of cyclosporine A (5
µM) or sinomenine (100 µM), while absorption increased
in the jejunum (45% to 55%) and terminal ileum (80% to
86%) but not in the duodenum [27].
*
eff
P
*
eff
P
*
eff
P*
eff
P
Similarly, in the Caco-2 cell model, absorptive trans-
port of PF was significantly (P < 0.05) increased 38% by
sinomenine, 27% by verapamil and 41% by cyclosporine
A. In contrast, its secretory transport was significantly (P
< 0.01) decreased to 45% by sinomenine, 35% by vera-
pamil and 37% by cyclosporine A. MRP inhibitors MK-
571 and leukotriene C4 did not affect transport of PF.
Sinomenine was also shown to significantly increase the
absorptive transport of digoxin and significantly decrease
its secretory transport.
5. Conclusion
PF administered alone has a low bioavailability. How-
ever in the presence of other phytochemicals, either in
pure form or in single or multiple herb prescriptions, the
bioavailability or the pharmacokinetics profiles may or
may not be significantly enhanced. This could conse-
quently have direct impact on its pharmacological actions.
Different methods to determine the cause of its low
bioavailability have shown that PF is poorly absorbed
due to low lipophilicity, efflux through P-glycoproteins,
hydrolytic degradation in the intestine by intestinal brush
border LPH and certain esterases, as well as intestinal
bacteria and without hepatic metabolism. However, the
bioavailability may be improved with P-gp inhibitors
(sinomenine) and LPH inhibitors. Methods that could be
used to determine the mechanism of the low bioavailabil-
ity of a compound needs serious consideration to be able
to give good predictions about the in vivo course of the
compound. Further work needs to be done to confirm the
effect of glycyrrhizin acid on the improvement of the
bioavailability of PF using the Caco-2 cell model and/or
MDCK II-MDR 1 cells, and the four-site Perfusion mo-
del.
6. Acknowledgements
The Project Supported by Natural Science Foundation of
Tianjin (No. 12JCZDJC26100); Research Fund for the
Doctoral Program of Higher Education [RFDP, No.
20121210110011]; National Basic Research Program of
China (973 Program) [No. 2012CB724001]; Program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT, No.IRT0973).
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