European Journal of Drug Metabolism and Pharmacokinetics

https://doi.org/10.1007/s13318-018-0509-3

REVIEW ARTICLE

Pharmacokinetics and Bioavailability Enhancement of Baicalin:

A Review
Ting Huang1,2 · Yanan Liu1 · Chengliang Zhang1

© Springer Nature Switzerland AG 2018

Abstract
Baicalin is one of the major bioactive components of Scutellaria radix, a Chinese herb that has been used since ancient
times. Baicalin has various pharmacological activities, including antitumor, antimicrobial, and antioxidant, and has wide
clinical applications. Baicalin displays a distinct pharmacokinetic profile including gastrointestinal hydrolysis, enterohepatic
recycling, carrier-mediated transport, and complicated metabolism. The in vivo disposition of baicalin is affected by com-
binations of other herbs and baicalin can interact with other co-administered drugs due to competition between metabolic
enzymes and protein binding. Furthermore, baicalin exhibits altered pharmacokinetic properties under different pathological
conditions. Due to its low bioavailability, emerging novel baicalin preparations including nano/micro-scale baicalin delivery
systems show better absorption and higher bioavailability in preclinical studies, and show promise for future clinical appli-
cations. Thus, this current review offers a comprehensive report on the pharmacokinetic behavior of baicalin and strategies
to improve its bioavailability.

Key Points  1 Introduction

The pharmacokinetics of baicalin mainly involve gas-
trointestinal hydrolysis, enterohepatic recycling, carrier-
mediated transport, multiple metabolism pathways, and
excretion in bile and urine.
Co-administration of baicalin with other herbs/drugs
may affect its in vivo properties and some pathological
conditions can also alter its pharmacokinetics.
New baicalin preparations have been developed to
improve its bioavailability, targeting, and therapeutic
efficacy.
Ting Huang and Yanan Liu contributed equally to this work.
* Chengliang Zhang
ph3719@aliyun.com
1 ated transport through cell membranes [4], different meta-
Department of Pharmacy, Tongji Hospital, Tongji Medical
College, Huazhong University of Science and Technology,
Wuhan 430030, China
2
Institute of Pharmaceutics, College of Pharmaceutical
Sciences, Zhejiang University, Hangzhou 310058, China
Traditional Chinese medicine (TCM) has a long history of
application in healthcare in China. As a widely used TCM,
Scutellaria radix (SR) has been applied in the medical treat-
ment of dysentery, hypertension, hemorrhage, insomnia, and
inflammation [1]. Flavonoids are considered to be the main
chemical components of SR, among which baicalin is an
essential active component used as the major phytochemi-
cal marker for the quality control of SR. Modern science
has shown that baicalin possesses significant pharmaco-
logical properties, including antitumor, antimicrobial, and
antioxidant activity [1], which contribute to its extensive
clinical use. Understanding the pharmacokinetics of baicalin
is essential for its safety and efficacy in clinical applica-
tions. Therefore, numerous studies have been conducted on
the pharmacokinetic profile of baicalin to clarify its in vivo
properties.
Pharmacokinetic studies have demonstrated the complex
properties of baicalin in vivo and its hydrolysis in the gastro-
intestinal tract [2], enterohepatic recycling [3], carrier-medi-
bolic pathways in systemic circulation [5], and excretion in
bile and urine [3, 6]. It has also been found that baicalin
has low bioavailability (2.2%), which could limit its clinical
efficacy [3]. Moreover, co-administered drugs and certain

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diseases also have a great impact on the pharmacokinetics
of baicalin. Some potential interactions between baicalin
and co-administered drugs have been elucidated and the
underlying mechanism is helpful for minimizing the risks
in combined therapy [7]. Furthermore, the pharmacokinetic
study of baicalin in pathology can be used as a reference for
evaluating its treatment efficacy [8].
A comprehensive understanding of the overall pharma-
cokinetic profiles of baicalin can assist in establishing the
pharmacokinetic–pharmacodynamic model and verifying
the therapeutic outcomes, thus providing a more reasonable
dosage regimen [9]. This review presents an overview of
recent research on the pharmacokinetic profiles of baicalin
in monotherapy and combined therapy, and sheds light on
possible strategies for improving its bioavailability.
2 Pharmacokinetic Characteristics
of Baicalin
2.1 Absorption
As a glycosidic flavone, baicalin is too polar to traverse the
lipid bilayer by passive diffusion and is thus poorly absorbed
in the intestinal tract (Fig. 1). However, the aglycone form
of baicalin, baicalein, demonstrates good permeability due
to its good lipophilicity and is well absorbed in the gastro-
intestinal tract [4]. Liu et al. [10] compared the absorption
mechanisms of baicalin and baicalein in rats and found that
baicalin was moderately absorbed in the stomach but poorly
in the small intestine and colon, while baicalein had better
absorption than baicalin in all segments of the gastrointes-
tinal tract. However, baicalin, rather than baicalein, is the
major component in the systemic circulation following oral
administration of baicalein [11]. According to a single-dose
Fig. 1  The structure of baicalin
T. Huang et al.
trial of baicalein in healthy adults, baicalein presented low
system levels, while baicalin was the most abundant metabo-
lite conjugate with maximum concentration (Cmax) values
10 times higher than those of baicalein [11]. Considerable
research [2, 4, 12] has suggested that a mutual transforma-
tion between baicalin and baicalein occurs in the absorption
process of baicalin. After administration, baicalin can be
easily hydrolyzed to baicalein by β-glucuronidase derived
from intestinal bacteria, while baicalein can be restored
to baicalin by UDP-glucuronosyltransferase (UGT) in the
systemic circulation [13]. Since baicalein is absorbed better
than baicalin, the conversion of baicalin to baicalein is a key
step for the absorption process of baicalin. Intestinal bacteria
were found to be a critical determinant for the conversion of
baicalin to baicalein after oral treatment, as the absorption of
baicalin is significantly lowered in germ-free rats compared
with conventional ones [14].
The absorption profile of baicalin showed bimodal or
even multiple peaks in many studies [15–17]. The rapid
appearance of the first peak suggests the rapid absorption
of baicalin [17, 18]. Several mechanisms have been given
to explain the bimodal phenomenon, with early research
suggesting that the multiple peaks are probably related to
the enterohepatic circulation. For example, Xing et al. [3]
reported that the plasma concentration–time profile of baica-
lin in bile donor rats did not display a second peak like that
observed in intact rats after oral or intravenous administra-
tion of baicalin.
Later, some researchers also proposed that other factors,
including different absorption sites, glucuronidation, and
variable gastric emptying [19–22], may be involved. The
intestinal absorption experiment showed that the absorption
rate of baicalin was segment-dependent [22] and that bai-
calin was first absorbed directly in the upper intestinal tract
in its initial form and later absorbed in the colon in the form
of aglycone [19]. Hence, the multiple absorption peaks of
baicalin involve various complicated mechanisms.
2.2 Distribution
Human plasma protein binding plays an important part in the
disposition of drugs in vivo, as the ratios of free fractions
determine the membrane transport rate and drug distribution
volume. Baicalin is absorbed rapidly into the plasma, but
can maintain its concentration at a certain range in plasma.
This may be due to its high protein-binding rate [18], which
was found to be 86–92% [23]. As the most abundant car-
rier protein in human plasma protein, human serum albumin
(HSA) represents a major transport medium for flavones like
baicalin. Liu et al. [24] found that baicalein had relatively
high affinity for HSA, while baicalin had moderate affin-
ity for HSA and could be converted into a relatively high-
affinity binder via the cleavage of a glycoside moiety. Thus,
Pharmacokinetics and Bioavailability Enhancement of Baicalin
the metabolism of baicalin can also exert an impact on its
distribution.
Baicalin’s high polarity limits its transportation through
the lipid bilayer via simple diffusion. Therefore, carrier-
mediated transport is essential to baicalin’s distribution.
Zhang et al. and Kalapos-Kovács et al. identified multid-
rug-resistant protein (MRP) 3 and MRP4 as the basolateral
transporters of baicalin, and MRP2 and the breast cancer
resistance protein (BCRP) as the apical transporters of bai-
calin [4, 25]. The affinities of baicalin to transporters were
found to be in the order BCRP > MRP3 > MRP2 > MRP1
[25]. Since many mutations of MRP2 exist in humans, it
has been inferred that baicalin disposition may vary among
individuals [26]. Nevertheless, correlations between MRP2
mutations and baicalin disposition have not yet been verified,
and require further investigation.
Baicalin was found to accumulate in various tissues. A
tissue distribution study of baicalin following intravenous
administration of an injectable solution showed that the
concentration of baicalin was highest in the kidneys, while
baicalin accumulated most in the lungs after intravenous
administration of liposomal baicalin [27]. Moreover, another
study found that baicalin in the Huang-Lian-Jie-Du-Tang
preparation had a higher concentration in the lungs than in
the kidneys or liver following oral administration in middle
cerebral artery occlusion (MCAO) rats. This was consistent
with its pharmacological sites of action. Such differences
may be caused by different routes of administration, different
preparations or the multiple herbs present in the decoction
[28].
Whether baicalin can cross the blood–brain barrier
(BBB) is controversial. In early pharmacokinetic studies, it
was found that baicalin could not cross the BBB, whereas
baicalein can be detected in the brain following administra-
tion [29, 30]. However, recent research reported that both
baicalin and baicalein could pass through the BBB, and the
passage of baicalin would probably require active transport-
ers such as organic anion-transporting polypeptide (OATP)
1A2 and OATP2B1 [31]. Furthermore, Zhang et al. [32]
found that the distribution of baicalin in the brain was a
subsequent process and that baicalin tended to accumulate
in the striatum, thalamus and hippocampus at different rates
and quantities. Another study, using a rapid and sensitive
ultra-performance liquid chromatography–tandem mass
spectrometry method, also proved that baicalin was able to
penetrate the BBB and distribute rapidly in the brain cer-
ebrospinal fluid [33]. Thus, these inconsistent results may
be attributable to the sensitivity of the assay methods. In
addition, it has been proposed that flavonoid conjugates tend
to be metabolized to their aglycones prior to entering the
brain. Thus, the conversion of baicalin may account for the
presence of baicalein in the brain and for the low brain con-
centration of baicalin [31].
2.3 Metabolism
The metabolism of baicalin can impact its efficacy and even
its toxicity. As mentioned previously, mutual transforma-
tion between baicalin and baicalein exists in the absorption
of baicalin with the involvement of key metabolic enzymes
including β-glucuronidase and UGT [2]. To further verify
the metabolism of baicalin, many researchers have studied
the other metabolites of baicalin [34–36]. Due to the limita-
tions of detection techniques, previous studies only obtained
a few key metabolites, including baicalin, baicalein, baica-
lein 6-O-β-d-glucopyranuronoside, and baicalein 6,7-di-O-
β-glucopyranuronoside [34, 35]. By using a more efficient
strategy, Zhang et al. [5] conducted a comprehensive study
profiling and identifying the metabolism of baicalin in
plasma and urine samples of rats. Meanwhile, the distribu-
tion of baicalin in various tissues was also elucidated. In
contrast to previous studies, this research focused on major-
to-trace metabolites of baicalin and thus discovered various
new metabolites. The study identified a total of 32 metabo-
lites in rat samples, of which 23 metabolites were detected
in rat urine and 26 in rat plasma. For the tissue distribution,
kidney and liver contained the most metabolites, viz. 10 and
9 metabolites, respectively, while only five metabolites could
be observed in heart, spleen, lung, and brain. This indicates
that the main organs for baicalin metabolism were the liver
and kidney. Comparing the structures of these metabolites, it
can be concluded that the major active metabolic sites were
the hydroxyl groups on the A ring and 8- and 4′-positions of
baicalin. Also, it was discovered that baicalin predominantly
underwent methylation, hydrolysis, hydroxylation, methox-
ylation, glucuronide conjugation, sulfate conjugation, and
their composite reactions [5] (the proposed metabolism is
shown in Table 1). So far, several metabolic enzymes have
been found to be involved including β-glucuronidase, UGT,
sulfatase and catechol-O-methyltransferases [13, 34–36].
Concomitant chemicals may affect the metabolic pathway
of baicalin. A total of 27 baicalin metabolites in rat plasma,
urine, and bile were defined after co-administration of emo-
din, baicalin, and geniposide in rats, among which three
metabolites that underwent glutathione conjugation were
different from the preceding research [37].
2.4 Excretion
Baicalin is primarily excreted in bile in the form of glucu-
ronides with high biliary excretion [3]. MRP2 is one of the
main transporters to mediate baicalin’s biliary efflux [4].
When baicalein was injected into the portal vein of MRP2-
deficient rats, a significant decrease in the biliary excretion
of baicalin occurred along with a large increase of baicalin
in the systemic circulation [26]. This highlights the critical
 T. Huang et al.

Table 1  Metabolism pathway of baicalin

R1 R2 R3 R4 R5

–OH –OH –H –OH –H

–OCH3 –OSO3H –OH –OSO3H –OH
–OGluA –OCH3 –OSO3H –OCH3 –OCH3
–OGluA –OCH3 –OGluA
–OGlc –OGluA
–OGlc

GluA glucuronic acid, Glc glucose

role of biliary excretion in the regulation of the pharmacoki-
netics of baicalin.
As an alternative excretion pathway, the fraction of baica-
lin excreted in urine appears to be minimal compared to the
biliary route [3]. The metabolites of renally excreted baicalin
were predominantly in the form of the parent drug and sul-
fated and hydroxylated compounds [38]. Lai et al. found that
following oral administration of SR in humans, 7.2% of the
dose was excreted in urine in the form of conjugated baica-
lein. The low urinary recovery of the conjugated metabolites
from the dose may have been caused by the remaining frac-
tion of the dose excreted in bile [6].
3 Pharmacokinetics of Baicalin in TCM
Formula
To improve the therapeutic effects, different herbs are usu-
ally combined to produce the TCM formula. The interactions
of herbs in the prescription may alter the pharmacokinetics
of the ingredients used. As a major component of the TCM
formula, SR is widely prescribed with herbs such as Coptidis
rhizoma, Paeoniae alba radix, and Bupleuri radix. Further-
more, prescriptions such as Huang-Lian-Jie-Du-Tang, San-
Huang-Xie-Xin-Tang, and Xiao-Chai-Hu-Tang have been
applied in medical care in China since ancient times. The
combined use of different herbs can lead to opposing results
on the absorption, distribution, metabolism, and excretion
of baicalin (the effects of TCM on the pharmacokinetics of
baicalin are summarized in Table 2).
A combination of Coptidis rhizoma and SR is the most
popular medicine in TCM. However, as a classic “heat-
ing-clearing” herb, Coptidis rhizoma has broad-spectrum
antibacterial activity that can inhibit the β-glucuronidase
activity of intestinal bacteria and reduce the absorption of
baicalin. Moreover, the main constituent of Coptidis rhi-
zoma, berberine, is an alkaloid and creates a complexation
reaction with baicalin [39]. The in situ rat intestinal perfu-
sion, Caco-2 cell monolayer transport, and small intestinal
flora incubation experiments revealed that the combination

Table 2  The influences of TCM on the pharmacokinetics of baicalin

Prescription or herb-couple Pharmacokinetic changes of baicalin Mechanism of herb–herb interaction References

Huang-Lian-Jie-Du-Tang Cmax↓, t1/2↑, AUC↓ Chemical reaction and inhibition of β-glucuronidase [19]
Xiao-chai-hu-Tang Cmax↓, t1/2↓, AUC↓ Competition or inhibition activities between the components [42]
Scutellariae–Coptidis couple Cmax↓, t1/2↑, AUC↓ Chemical reaction and inhibition of β-glucuronidase [41]
Chaiqin Qingning Capsules Cmax↓, t1/2↑, CL↓, AUC↓, MRT↑ Prolonged metabolism and slower elimination of baicalin [43]
Scutellariae–Paeoniae couple Cmax↑, t1/2↑, AUC↑, MRT↑ Improved function of spleen, digestive system vitality and [78]
immune system
Scutellariae–Angelicae couple Papp↑ Opening of the tight junctions between cells and inhibition [44, 45]
of MRP expression or function
Scutellariae–Panax couple Cmax↑, t1/2↓, CL↓, AUC↑, MRT↓ Increased distribution and reduced elimation [46]

Cmax maximum concentration, t1/2 half-life, AUC​area under the curve, CL clearance, MRT mean retention time, Papp apparent permeability coef-
ficien, MRP multidrug-resistant protein, ↑ increase, ↓ decrease
Pharmacokinetics and Bioavailability Enhancement of Baicalin
of berberine decreased the absorption and metabolism of
baicalin, although no effect on the transport profile of
baicalin across the Caco-2 cell was seen [40]. However,
another study showed that the combination of Coptidis
rhizoma and SR resulted in a reduction in the transport of
baicalein from the mucosal side to the serosal side [41].
Although the chemical reaction between baicalin and the
active ingredients of Coptidis rhizoma can decrease the
systemic exposure level of baicalin, the two herbs are fre-
quently prescribed in multiple remedies, such as Huang-
Lian-Jie-Du-Tang and San-Huang-Xie-Xin-Tang, for the
purpose of decreasing the side effects of Coptidis rhizome
[19, 40]. In addition, Xiao-Chai-Hu-Tang, another impor-
tant multiherbal medicine which also contains an alkaloid,
could also cause a decrease in the absorption of baicalin
and an increase in its elimination [42]. Thus, it can be
concluded that the combination of baicalin and alkaloids
in prescriptions may reduce the absorption of baicalin.
Many prescriptions which perform synergistic effects
and promote the bioavailability of baicalin also exist.
Chaiqin Qingning capsules, which contain baicalin,
Bupleuri radix, and calculus bovis factitious, were found
to have greater anti-fever effects than baicalin alone. This
may be attributed to the prolonged metabolism and slower
elimination of baicalin in the Chaiqin Qingning capsule
[43]. Furthermore, baicalin in the combined Scutellar-
iae–Paeoniae extract has shown better absorption than
pure baicalin and SR extract, which may be ascribed to the
ability of Paeoniae alba radix to improve digestive system
vitality and exert a harmonizing effect on the absorption
of baicalin [18]. Moreover, the intestinal absorption of
baicalin can be enhanced by Angelicae dahuricae radix
due to the co-administered herb’s ability to open the tight
Table 3  Effect of baicalin on the pharmacokinetics of coadministrated drugs
Probe drug Pharmacokinetic changes of probe drug
Phenacetin Cmax↓, t1/2↑, V↑, CL↓, AUC↑
Theophylline Cmax↓, t1/2↑, V↑, the changes in CL and AUC
depended on the regime
Chlorzoxazone Cmax↓, t1/2↑, V↑, CL and AUC were not affected
Dextromethorphan Cmax↑, no significant changes in t1/2, V↓, CL↓, AUC↑ Competitive binding of plasma protein binding and
Midazolam Cmax↑, t1/2↑, V↓, CL↓, AUC↑,
Nifedipine Cmax↓, the changes of t1/2 depended on the regime, V↑, Competitive binding of plasma protein binding and
CL↑, AUC↓
Caffeine Not affected by baicalin
Rosuvastatin t1/2↓, CL↑, AUC↓
Cmax maximum concentration, t1/2 half–life, V apparent volume of distribution, CL clearance, AUC​area under the curve, CYP cytochrome P450,
↑ increase, ↓ decrease
junctions between cells and inhibit MRP efflux protein
expression or function [44, 45]. Interestingly, the combina-
tion of Panax notoginsenosides with baicalin can promote
the penetration of baicalin into the rat brain, increasing the
concentration and slowing down the elimination of baica-
lin from rat brain and plasma [46]. The above outcomes
indicate that a rational combination of herbs can improve
the bioavailability of baicalin and its subsequent efficacy.
4 Drug Interactions of Baicalin
The disposition of baicalin in vivo involves various drug
transporters and metabolic enzymes, which may be influ-
enced by co-administered drugs or have an influence on
co-administered drugs in return. These factors contribute to
the extensive herb–drug interactions between baicalin and
chemical drugs. Attention is given to antibiotics when they
are co-administered with baicalin, since they may exert an
impact on the pharmacokinetic profile of baicalin by inhibit-
ing intestinal bacteria [47]. In addition, many studies have
been performed on the effects of baicalin on the pharmacoki-
netics of co-administered drugs, and the relevant research is
summarized in Table 3.
Baicalin can significantly change the pharmacokinetics
of drugs which share the same cytochrome P450 (CYP)
enzymes or high protein binding. Qiao’s team elucidated the
effects of baicalin on phenacetin, theophylline, midazolam,
dextromethorphan, nifedipine, and chlorzoxazone involving
metabolism by CYP1A2, CYP2E1, CYP3A, and CYP2D.
The values of inhibition constants (Ki) of baicalin in rats
were estimated to be 88.1, 145.8, 105.6, and 155.6 mM for
CYP1A2, CYP2E1, CYP3A, and CYP2D, respectively,
Mechanism of drug–herb interaction References
Competitive binding of plasma protein binding and [51]
CYP1A2 inhibition
Competitive binding of plasma protein binding and [50, 56]
CYP1A2 inhibition
Competitive binding of plasma protein binding and [48]
CYP2E1 inhibition
[7]
CYP3A inhibition
CYP3A inhibition [49]
[53, 57]
CYP3A inhibition
Plasma concentration of baicalin was not enough for [52]
CYP inhibition
CYP inhibition [79]

which indicated relatively weak inhibition ability. The man-
ner of inhibition of baicalin was competitive for CYP3A and
CYP2E1, non-competitive for CYP2D, and mixed-type for
CYP1A2, and the effects of baicalin on different substrates
of different CYP subtypes were also different [7, 48–50].
Baicalin was found to exhibit large inter-individual vari-
ation on the inhibition of CYP1A2 that had no relationship
with gene polymorphism [50, 51]. In regard to the CYP1A2
substrates, the pharmacokinetic parameters of phenacetin
and theophylline including Cmax, half-life (t1/2), and apparent
volume of distribution (V) were both influenced by baica-
lin. Baicalin significantly inhibited the metabolism of phen-
acetin, which was stronger than that for theophylline: the
clearance (CL) of phenacetin decreased and the area under
the curve (AUC) increased while theophylline showed no
significant change to CL and AUC with the same baicalin
dosage (450 mg/kg at 0 h). The discordant results might be
attributed to a decrease in plasma protein binding of theo-
phylline caused by competitive binding by baicalin, and a
subsequent increase in unbound theophylline and hepatic
clearance [50, 51].
Baicalin was shown to inhibit CYP2E1 in  vitro, but
exerted no effect on the AUC and CL of chlorzoxazone
(probe drug of CYP2E1) in vivo [48]. Furthermore, in vivo
protein-binding experiments found that the plasma free
fraction of chlorzoxazone increased 2.6-fold immediately
after baicalin administration. Thus, it can be inferred that
the increased hepatic clearance caused by the increased free
fraction of chlorzoxazone contributed to the unchanged AUC
and CL levels [48]. It is noteworthy that the plasma concen-
tration of baicalin is a crucial determinant for enzyme inhi-
bition and that certain dosages of baicalin may not achieve
a suitable capacity to inhibit the CYP enzyme in vivo [52].
Since CYP3A enzymes accommodate multiple ligands
in the active site, more than one probe drug was used to
study the resultant interactions with baicalin [7, 49, 53]. The
AUC and Cmax of dextromethorphan and midazolam were
increased and the CL was decreased following concomitant
administration with baicalin. Baicalin was also found to
alter the pharmacokinetics of nifedipine, another CYP3A
substrate, in a different way. The Cmax of total nifedipine
and the AUC decreased while the CL increased. The results
might also be explained by increased unbound nifedipine
and hepatic clearance, as the ability of baicalin to displace
drugs from plasma proteins varied among the competing
drugs.
The high plasma protein-binding rate of baicalin may
influence the binding of other drugs. The binding affinity
of theophylline, nifedipine, promethazin,e and cleviprex
to HSA may decrease in combined therapy with baicalin
due to competitive binding to the same site [54–57]. Inter-
estingly, the binding affinity of curcumin to HSA can be
increased in the presence of flavonoids such as baicalin by
T. Huang et al.
simultaneously binding in different regions of site I of HSA
to form a ternary complex [58]. The alterations in HSA bind-
ing rate and the inhibition of CYP enzymes by baicalin, as
mentioned above, may occur together in combined therapy
and complicate the pharmacokinetic process of co-adminis-
tered drugs. Further investigations are required to ascertain
the possible mechanisms of herb–drug interactions which
would be beneficial for minimizing the adverse drug reac-
tions in clinical settings.
5 Disease Influences
on the Pharmacokinetics of Baicalin
Pathological conditions may alter the functions of many
enzymes and transporters, which may then influence drug
pharmacokinetics in vivo. Since baicalin has been proven
to have an anti-diabetic effect and is used as an adjunctive
therapeutic agent in diabetes therapy [59], its pharmacoki-
netic profile in diabetic models is of interest to research-
ers. A higher baicalin plasma concentration and lower
baicalin urine concentration were found in type 2 diabetic
rats compared to normal rats due to the elevated intes-
tinal β-glucuronidase activity under diabetic conditions
[60]. It should be noted that no differences in metabolite
classes of baicalin between normal and type 2 diabetic
rats, either in plasma or urine samples, were observed.
TCM prescriptions containing SR, such as Huang-Lian-
Jie-Du-Tang and San-Huang-Xie-Xin-Tang, also showed
the same pharmacokinetic changes of baicalin in type 2
diabetic rats [61, 62].
Enhanced absorption of baicalin was also found in
ulcerative colitis [18], MCAO [39], cerebral ischemia–rep-
erfusion [8], and intrahepatic cholestasis [63], the under-
lying mechanism of which may be due to the altered
β-glucuronidase, UGT, MRP2, intestinal or hepatic meta-
bolic enzymes, and bile flow rate in the pathological con-
dition. However, as for febrile rats, the absorption and
elimination of baicalin were decreased by the inhibited
metabolic enzyme activities when fever was present [43].
The changed absorption and elimination of baicalin should
raise concerns regarding the dosage adjustment of baicalin
and potential safety [38].
6 Strategies for Improving
the Bioavailability of Baicalin
Baicalin has been shown to have various pharmacologi-
cal effects. However, in some cases its low bioavaila-
bility limits its clinical efficacy. Therefore, it is impor-
tant to improve the bioavailability of baicalin. With the
Pharmacokinetics and Bioavailability Enhancement of Baicalin

Table 4  Novel baicalin preparations effective than other nanoparticles, which could be due to
Novel baicalin preparation Cmax AUC References the enhanced permeability induced by surfactants and
increase increase cosurfactants, the sustained release of baicalin [68], and
(fold) (fold) the increased uptake of baicalin by lymphatic transport
[71].
Liposome 2.82 2.81 [64]
Other strategies have also been developed for improving
BN-PEG-NLC – 7.20 [65]
the bioavailability of baicalin, including phospholipid com-
OX26-PEG-CSLN 7.88 11.08 [70]
plexes [72], solid dispersion [73], inclusion complexes [74],
Nanocrystal 2.47 2.04 [81]
and micelles [75]. Like liposomes, the phospholipid com-
Nano-emulsion I 4.05 7.20 [68]
plex can improve the solubility and permeability of baica-
Nano-emulsion II 3.39 14.56 [71]
lin. Moreover, nasal administration of baicalin phospholipid
Combination of phos- 2.03 2.27 [76]
pholipid complex and complex can improve brain uptake of baicalin through the
SMEDDS olfactory pathway, which can enhance the therapeutic out-
Solid dispersion 4.62 3.38 [80] comes of cerebral disease [72]. Although phospholipids can
Inclusion complex 2.21 2.53 [74] significantly increase membrane transport, the overly high
Micelle 1.17 1.54 [75] lipophilicity of phospholipids could lead to a poorer dis-
persion in aqueous media, such as the gastrointestinal tract.
BN-PEG-NLC PEGylated nanostructured lipid carriers, OX26-PEG-
CSLN OX26-PEGylated cationic solid lipid nanoparticles, SMEDDS Self-emulsifying micro-emulsion (SMEDDS) possesses the
self-emulsifying microemulsion, AUC​ area under the curve, Cmax advantages of improving dissolution and diffusion, and facil-
maximum concentration itating intestinal lymphatic transport of drugs. The combined
use of a phospholipid complex and SMEDDS would remedy
the disadvantages of the phospholipid complex by balancing
development of preparation techniques, newly developed the lipophilicity and hydrophilicity of drugs, and thus greatly
baicalin preparations exhibit better absorption and thus improving the absorption of baicalin in the gastrointestinal
have higher bioavailability. We have summarized the tract [76]. In addition, solid dispersion technology and inclu-
research progress in improving the bioavailability of bai- sion complex formulation can both increase the dissolution
calin and listed the novel strategies in Table 4. rate of baicalin and improve its oral bioavailability [73, 74,
Nanonization technology is a promising preparation 77]. Moreover, mixed micelles containing Pluronic P123
strategy for improving the bioavailability of poorly water- copolymer and sodium taurocholate, as carrier materials,
soluble drugs as it can improve the dissolution rates and can also improve oral bioavailability of baicalin and even
solubility of insoluble drugs. Various nanonization prepa- increase baicalin uptake by cancer cells [75].
rations of baicalin have been studied, including liposomes Among the various preparations, nano-emulsions and
[64], nanostructured lipid carriers/solid lipid nanoparti- SMEDDS showed superior enhancement in the bioavailabil-
cles [65, 66], nanocrystals [67], and nano-emulsions [68]. ity of baicalin due to their unique characteristics. Compared
Liposomes are known to increase drug solubility and sta- with the oral route, parenteral administration of baicalin
bility and serve as an effective drug delivery system for preparations can provide advantages, such as improvements
poorly soluble drugs like baicalin. Compared with baicalin in brain uptake, and could thus be used as an alternative
suspensions, baicalin-liposomes improved oral bioavail- administration route according to clinical needs. Further-
ability as well as the tissue distribution of baicalin [64]. more, modified preparations could further improve their
To improve tumor targeting and prolong the retention targeting ability and improve therapeutic efficacy.
time in vivo, baicalin-liposomes can be further modified
with folate and polyethylene glycol (PEG). The modified
liposomes exhibited a high colloidal stability and showed 7 Conclusion and Prospects
a much higher cellular uptake than non-targeted liposomes
[69]. Likewise, baicalin-loaded PEGylated nanostruc- As one of the major active components of SR, baicalin is
tured lipid carriers (BN-PEG-NLC) [65] and OX26 (an more promising than its aglycone and is widely applied in
antibody which can enhance drug penetration across the TCM because of its good stability and bioactivity. However,
BBB)–PEG–cationic solid lipid nanoparticles (CSLN) [66, baicalin undergoes extensive first-pass metabolism, has low
70] have been designed to improve targeting efficacy, and bioavailability and a short half-life due to the glycosyl group
the AUCs of these new preparations were significantly on the ring. Although many studies have been conducted
enhanced. Nanocrystals and nano-emulsions of baicalin on the pharmacokinetics of baicalin, there are still some
have also been studied extensively [67]. It is worth not- uncertainties regarding its effects. For example, there are
ing that baicalin-loaded nano-emulsions seem much more controversial results on the transport pathway of baicalin

and its ability to cross the BBB. Moreover, while most of the
metabolites of baicalin have been tentatively identified, the
pharmacological contributions of the metabolites remain to
be investigated. As previous studies were restricted by the
sensitivity of detection methods, a sensitive and appropriate
assay method is still needed for the precise pharmacokinetic
10. Taiming L, Xuehua J. Investigation of the absorption mechanisms
demonstration of baicalin.
Since baicalin is frequently prescribed with other medica-
tions, understanding the compatibility of co-administrated
herbs/drugs is of importance for clinical applications,
and requires further research for better clarity. Further-
more, pharmacokinetic changes of baicalin under different
pathological conditions indicate clinical considerations of
drug safety and the possible requirement of individualized
therapy. Due to its low bioavailability, novel preparation
methods have been applied to improve the bioavailability
of baicalin in order to enhance its pharmacological effects.
These novel baicalin preparations are currently in preclinical
studies, and whether they can be used in the clinic deserves
further evaluation.
Compliance with Ethical Standards  15. Huang P, Gao JW, Shi Z, Zou JL, Lu YS, Yuan YM, Yao MC. A
Funding  No sources of funding were used to prepare this review.
Conflict of interest  All of the authors report no conflicts of interest.
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