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Bioavailability of Pentacyclic Triterpene
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199
prodrugs through oral gavage. Using Kinetica®, Version 4.4 (USA, Thermo
Electron Corporation, New York, NY), a standardized non-compartmental
study was used to estimate the absorption prole. The authors found that the
water solubility of oleanolic acid prodrugs was higher than that of oleanolic
acid itself. In rat permeability studies using a model of single-pass intestinal
perfusion, all of the prodrugs had greater membrane efcient permeability,
and in rats, 6f and 5a had increased oleanolic acid oral bioavailability (Figure
6.7) (Ganbold et al., 2010).
Figure 6.7: Cao et al. studied the chemical structure of oleanolic acid derivatives.
Source: https://pubmed.ncbi.nlm.nih.gov/22352697/.
The pharmacokinetic characteristics of dipeptide diester/two amino acid
prodrugs with a propylene glycol relation to oleanolic acid were established
by the same team of researchers in some other study (Qiang et al., 2011).
The ndings of this study indicated that a portion of the dipeptide diester
prodrugs of oleanolic acid/propylene glycol-linked amino acid had better
bioavailability, stability, permeability, and afnity than the dipeptide
diester prodrugs/ethylene glycol-linked amino acid synthesized by Cao et
al. (2013). Figure 6.3 depicts the chemical structures of these derivatives.
The absorption prole was estimated using Kinetica®, Version 4.4, using
standard non-compartmental analysis.
The pharmacokinetic parameters of oleanolic acid in rats after intravenous
insertion at 0.5, 1, and 2 mg/kg doses and oral administration at 10, 25, and
50 mg/kg doses were studied by Jeong et al. (2007). Following the incubation
with the liver microsomes of rats in the vicinity of NADPH, these authors
found that oleanolic acid was also metabolically not stable. The weak
bioavailability of 0.7% oleanolic acid estimated after administering orally
to rats, maybe due to weak absorption of gastrointestinal and corresponding
metabolism of hepatic microsomal.
Tong et al. (2011) calculated the pharmacokinetic parameters of certain
oleanolic acid formulations after oral administration of 50 mg/kg to rats. The
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authors estimated three various formulations: Formula G (Using spray freeze
drying and the incorporation of sodium caprate, strong oleanolic acid sodium
salt dispersion in polyvinylpyrrolidone-40 matrix), Formula F (Using spray
freeze drying and the incorporation of sodium caprate, strong oleanolic acid
sodium salt dispersion in polyvinylpyrrolidone-40 matrix), and Formula B
(Using spray freeze drying and the incorporation of sodium caprate, strong
oleanolic acid sodium salt dispersion in polyvinylpyrrolidone-40 matrix).
As Formulas B and G were compared, it was discovered that the addition
of sodium caprate culminated in an initial increase in plasma oleanolic
acid concentration, which peaked within the rst 13–18 minutes and then
gradually decreased. The effect of the sodium salt form on oleanolic acid
oral bioavailability was assessed by examining the ndings obtained with
Formulas G and F, and the researchers found that replacing oleanolic acid
with sodium salt had no substantial inuence on the concentration-time
prole of plasma or the related estimates of the kinetic parameter.
Jeong et al. (2007) created a self-nano emulsied oleanolic acid drug
delivery device and tested in vivo oral rats’ bioavailability, comparing this
formulation to an oleanolic acid pill available commercially. The authors
claim that the self-nano emulsied system of drug delivery for oleanolic
acid resulted in a 2.4-fold improvement in oral bioavailability and oleanolic
acid’s retention time in rat plasma.
Hu and Li (2011) dened two techniques for increasing oleanolic acid oral
bioavailability. They conducted a pharmacokinetic analysis using a complex
of solidied phospholipid (oleanolic acid phospholipid complex (OPCH))
made up of hydroxyapatite and a complex oleanolic acid phospholipid,
as well as the same complex with ketoconazole (KCZ), a noncompetitive
CYP3A enzyme inhibitor. The rats were given 50 mg/kg of oleanolic
acid, OPCH and OPCH added with KCZ through oral administration. By
enhancing permeability and solubility and including inhibition of oleanolic
acid metabolism, the preparation of co-administration of KCZ and solidied
phospholipid complex increased the oleanolic acid bioavailability.
To improve the bioavailability and solubility of oleanolic acid, Yang et
al. (2010) established a self-drug delivery mechanism, and pharmacokinetic
analysis in rats was conducted to equate the developed one to the traditional
formulation of the tablet. By maintaining the drug in a dissolved state, the
self-micro emulsifying drug delivery mechanism improved the oleanolic acid
bioavailability to 507%, which helped to improve absorption. A ne water/
oil microemulsion is formed by the established drug delivery mechanism.
Bioavailability of Pentacyclic Triterpene
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With less than 100 nanometers size of the droplet, the medication has
a high interfacial surface area. According to the authors, the high content
of surfactant in the formed formulation can also improve permeability by
disrupting the cell membrane.
Jeong et al. (2007) developed a nanosuspension of oleanolic acid-stable
by sucrose ester and conducted pharmacokinetic trials in rats after intravenous
(2 mg/kg) and oral (10 and 20 mg/kg) administration. The authors linked
the formulated formulation to a coarse suspension of oleanolic acid. The
oleanolic acid nanosuspension had a 6–7-fold higher oral bioavailability
than the coarse suspension of oleanolic acid.
Raisins and Grape skins are also sources of oleanolic acid (Vitis vinifera
L.). Sánchez et al. (2006) found that 4 hours after eating 144 g of raisins,
the amount of oleanolic acid in human plasma approached its maximum
concentration (24.4 ± 14.4 ng/mL).
Rodriguez-Rodriguez et al. (2015) conducted pharmacokinetic
experiments on oleanolic acid in beagle dogs. They evaluated oleanolic
acid pharmacokinetic parameters following the intravenous and oral
administration of calenduloside E, and oleanolic acid triterpene saponin and
glucuronic acid were conjugated, while some researchers used supercritical
uid technology to determine the parameters of pharmacokinetic for a
stable distribution of oleanolic acid processed with fumed silica (Jeong et
al., 2007). According to some researchers, after ingestion of calenduloside
E oral doses, oleanolic acid was detected in the plasma, meaning that it
is formed from the conjugate of glucuronic acid (Ovesná et al., 2004). In
fact, after forming in the gut, oleanolic acid is absorbed and transferred
to the liver, where it is transformed into a conjugate of glucuronic acid.
This conjugate is excreted by the bile and transferred to the gut, where it is
hydrolyzed again to oleanolic acid, and the cycle begins again. RodriguezRodriguez et al. (2015) found that the strong distribution of oleanolic acidtreated with fumed silica had 1.9-fold higher bioavailability than industrial
tablets based on the AUC values.
The pharmacokinetic parameters of maslinic acid, the major pentacyclic
triterpene present in the fruits and leaves of Olea europaea L., were determined
(by different researchers) after oral (50 mg/kg) and intravenous (1 mg/kg)
administration of this triterpene to rats (Sharma et al., 2004). By using
population-based compartmental modeling with the nonlinear mixed-effects
method, plasma concentrations of maslinic acid against time were investigated
in a non-compartmental manner. Non-compartmental measurements
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validated the estimates. The compartmental and noncompartmental
approaches were used to approximate certain pharmacokinetic parameters
are: AUC
in intravenous manner; AUC
= 14.87 after oral administration; C
after intravenous injection; C
∞ µmol·h/L = 5.17 and AUC0→∞µmol·h/L = 5.06 after injection
0→
∞µmol·h/L = 12.43 and AUC0→∞µmol·h/L
0→
= 4.03 µM and C
max
= 17.61 µM and C0 = 32.79 µM
0
= 5.36 µM after oral
max
administration. Maslinic acid’s oral bioavailability was found to be 5.13%.
This lower bioavailability may be caused by the compound’s rst-pass
impact on the gut wall or liver, or by weak absorption of the gastrointestinal.
After intravenous administration of ursolic acid (15 mg/kg) dissolved in
a 10-mL mixture of polyethylene glycol 400 and ethanol (1:1) and ursolic
acid phospholipid nanoparticles (15 mg/kg), concentrations in plasma and
mouse tissues were determined. The plasma ursolic acid concentration
in phospholipid nanoparticles (2.07 ng/mL) was greater than the plasma
concentration of an ursolic acid solution (0.82 ng/mL) after 12 hours of
intravenous administration.
For enhancing the bioavailability and dissolution characteristics of
ursolic acid, other formulation strategies have been established. Yang et al.
(2010) used various procedures to make nanoparticles, and liposomes. These
scientists conducted pharmacokinetic experiments in rats and mice. Ursolic
acid nanoparticles oral bioavailability prepared to utilize D-tocopheryl
polyethylene glycol 1000 succinate was higher by 27.5-fold than that of the
free compound of ursolic acid (Yamaguchi et al., 2008).
The bioactive component of Centella Asiatica (L.) Urb. extracts are
Asiatic acid, a ursane form of triterpene that is sold by Syntex in a range of
Canada and European Union countries under the trade name Madecassol®
to treat a wide range of dermatological disorders, like burns (Rein et al.,
2013). C. asiatica contains Asiatic acid mostly as a free triterpene and as
asiaticoside (aglycone of the triterpenoid saponin is the triterpene Asiatic
acid). After orally administered equimolar doses of asiaticoside (24 mg)
and Asiatic acid (12 mg), the Asiatic acid bioavailability was tested in
12 stable female and male volunteers. The average AUC discrepancy
between medications was 2% less than (AUC012 h ng h/mL = 606,316
after administration of asiaticoside on Day 10 of a double daily regime
and AUC0→12 h ng·h/mL = 614 ± 250 after administration of Asiatic acid
on Day 10 of a double daily regime). Moreover, the C
administration of Asiatic acid was higher (C
the C
reached after administration of asiaticoside (C
max
reached after the
= 97.8 ± 43.5 ng/mL) than
max
max
= 65.1 ± 30.4 ng/
max
Bioavailability of Pentacyclic Triterpene
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203
mL), and the T
h) than the T
was marginally shorter on Asiatic acid (T
max
on asiaticoside (T
max
= 5.4 ± 4.3 h). As a result of the in
max
= 4.0 ± 2.5
max
vivo hydrolysis of asiaticoside into Asiatic acid, Asiaticoside adds to the
plasma levels of Asiatic acid following the administration of Madecassol®.
According to the researchers, the combination of asiaticoside and Asiatic
acid in Madecassol® ensures that Asiatic acid is available quickly and for a
long time, ensuring therapeutic efcacy over the dosage period.
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