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https://news5.thieme.de/r/r.aspx?AyADxKathsT0rKnazCb0FkxZSA2
Effective URL:
https://www.thieme-connect.com/products/ejournals/html/10.1055/a-2328-2644
Submission: On June 21 via api (June 21st 2024, 5:19:51 pm UTC) from HK — Scanned from DE

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      <li><a href="/products/ejournals/issue/10.1055/s-014-59723">07/08: Special Issue Judith M. Rollinger, Elke H. Heiß</a></li>
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      <li><a href="/products/ejournals/issue/10.1055/s-014-59464">05: 336-410</a></li>
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      <li><a href="/products/ejournals/issue/10.1055/s-014-59094">03: 172-251</a></li>
      <li><a href="/products/ejournals/issue/10.1055/s-014-58923">02: 84-165</a></li>
      <li><a href="/products/ejournals/issue/10.1055/s-013-58810">01: 4-80</a></li>
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Planta Med
DOI: 10.1055/a-2328-2644
Original Papers

POPULATION PHARMACOKINETIC OF THE DITERPENES ENT-POLYALTHIC ACID AND
DIHYDRO-ENT-AGATHIC ACID FROM COPAIFERA DUCKEI OIL RESIN IN RATS

Fábio Alves Aguila
1 Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de
Franca, Franca, Brazil
,
Jairo Kenupp Bastos
2 School of Pharmaceutical Sciences of Ribeirão Preto – University of São
Paulo, Ribeirão Preto, Brazil
,
Rodrigo C. S. Veneziani
1 Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de
Franca, Franca, Brazil
,
Glauco Henrique Balthazar Nardotto
2 School of Pharmaceutical Sciences of Ribeirão Preto – University of São
Paulo, Ribeirão Preto, Brazil
,
Larissa Costa Oliveira
1 Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de
Franca, Franca, Brazil
,
Adriana Rocha
2 School of Pharmaceutical Sciences of Ribeirão Preto – University of São
Paulo, Ribeirão Preto, Brazil
,
Vera Lucia Lanchote
2 School of Pharmaceutical Sciences of Ribeirão Preto – University of São
Paulo, Ribeirão Preto, Brazil

,
Sérgio Ricardo Ambrósio
1 Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de
Franca, Franca, Brazil

› Institutsangaben
Gefördert durch: Conselho Nacional de Desenvolvimento Científico e Tecnológico
Gefördert durch: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Gefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo
2011/13630-7

› Weitere Informationen
* Abstract
* Volltext
* Referenzen
* Abbildungen

als PDF herunterladen Lizenzen und Reprints
* Abstract
* Introduction
* Results and Discussion
* Material and Methods
* Plant materials and chemicals

* Development and validation of an analytical method for ent-polyalthic acid
and dihydro-ent-agathic acid in rat plasma
* LC-MS/MS analysis

* Preparation of standard solutions

* Sample preparation

* Method validation

* Population pharmacokinetics of ent-polyalthic acid and dihydro-ent-agathic
acid in rats
* Animal experiments

* Population pharmacokinetic models

* Contributorsʼ Statement
* References

ABSTRACT

Copaifera duckei oleoresin is a plant product extensively used by the Brazilian
population for multiple purposes, such as medicinal and cosmetic. Despite its
ethnopharmacological relevance, there is no pharmacokinetic data on this
important medicinal plant. Due to this, we determined the pharmacokinetic
profile of the major nonvolatile compounds of C. duckei oleoresin. The
diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to
approximately 40% of the total oleoresin. Quantification was performed using
LC-MS/MS, and the validated analytical method showed to be precise, accurate,
robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to
18.85 µg/mL plasma, respectively, for ent-polyalthic acid and
dihydro-ent-agathic acid, making it suitable for application in preclinical
pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose
(gavage) of C. duckei oleoresin, and blood was collected from their caudal vein
through 48 h. Population pharmacokinetics analysis of ent-polyalthic and
dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects
modeling conducted in NONMEN software. The pharmacokinetic parameters of
ent-polyalthic acid were absorption constant rate = 0.47 h−1, central and
peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively,
apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For
dihydro-ent-agathic acid, absorption constant rate = 0.28 h−1, central and
peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively,
apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent
clearance, central apparent volume of distribution, and peripheral apparent
volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-,
and 13.78-folds higher than those of dihydro-ent-agathic.

KEYWORDS

Copaifera duckei - dihydro-ent-agathic acid - ent-polyalthic acid - Leguminosae
- pharmacokinetic

INTRODUCTION

The Copaifera genus (Leguminosae), commonly known as “Copaíbas”, “Copaibeiras”,
or “Copaívas”, encompasses approximately 70 species of large trees that are
widely distributed in Brazil, primarily in the northern region, with a
particular emphasis on the states of Amazonas, Pará, and Roraima [1], [2], [3].
The oleoresins extracted from the trunk of these plants have long been utilized
in traditional Brazilian medicine, demonstrating various beneficial properties
such as anti-inflammatory, antimicrobial, analgesic, wound healing, antitumor,
purgative, and antiparasitic activities [1], [2], [3]. Moreover, these
oleoresins hold significant pharmacological value and are commercially sold as
crude oil to serve as raw material for producing cosmetics [1], [3], [4].

These oleoresins exhibit variable viscosity and color and comprise volatile
sesquiterpenes and nonvolatile acid diterpenes [1], [5]. Despite notable
variations in the chemical composition among Brazilian Copaifera species,
sesquiterpene compounds such as δ-cadinene, α-cadinol, α-cubebene, β-elemene,
α-copaene, α-humulene, β-caryophyllene, and caryophyllene oxide, as well as
kaurane, clerodane, and labdane diterpenes, have been identified in all examined
species [1], [6], [7].

Among the various Copaifera oleoresins found in Brazil, the oleoresin from
Copaifera duckei Dwyer is the most prominent representative of Amazonian
“Copaíbas”. This oleoresin comprises approximately 72% nonvolatile components,
including the diterpenes ent-polyalthic acid and dihydro-ent-agathic acid
[6], [7] ([Fig. 1]).

Fig. 1 Chemical structures of the major nonvolatile constituents of Copaifera
duckei oil resin: ent-polyalthic acid (1) and dihydro-ent-agathic acid (2).

In Brazilian folk medicine, the recommended oral dosage is 3 – 5 drops dispersed
in warm water or honey, taken up to three times daily to treat internal ailments
[8], [9]. Despite the oral administration of these oleoresins, there is a lack
of information regarding their pharmacokinetic studies. Consequently, we have
developed and validated an analytical method to determine the pharmacokinetic
profiles of ent-polyalthic and dihydro-ent-agathic acids in rat plasma samples
following a single oral dose of C. duckei oleoresin administration.

RESULTS AND DISCUSSION

The mass spectra in the mobile phase and the chromatograms of plasma samples of
the ent-polyalthic and dihydro-ent-agathic acids and the internal standard (IS)
warfarin are depicted in [Figs. 2] and [3]. The matrix effect, linearity,
precision, accuracy, and stability are shown in [Table 1]. The carryover tests
of the ent-polyalthic and dihydro-ent-agathic acids and the IS warfarin are
shown in [Fig. 3]. Chromatographic peak areas of the blank plasma samples were
lower than 20% of the lower limit quality control (LLQC) areas, as shown in
[Fig. 3].

Fig. 2 Full scan mass spectrum of Copaifera duckei oil resin,
dihydro-ent-agathic, ent-polyalthic acids, and warfarin sodium (internal
standard) diluted in the mobile phase. Fig. 3 Chromatograms of the lower limit
quality control (LLQC), low-quality control (LQC), and high-quality control
(HQC) samples and of blank plasma samples immediately following HQC sample
analysis of ent-polyalthic and dihydro-ent-agathic acids.
Table 1 Validation parameters of the method of analysis of ent-polyalthic and
dihydro-ent-agathic acids in rat plasma samples.

Table 1 Validation parameters of the method of analysis of ent-polyalthic and
dihydro-ent-agathic acids in rat plasma samples.

NMF = normalised matrix factor, CV = coefficient of variation, RSE = relative
standard error, LLQC = lower limit of quantification, LQC = low-quality control,
MQC = medium quality control, HQC = high-quality control

Parameter

ent-Polyalthic acid

Dihydro-ent-agathic acid

Matrix effect
Mean NMF (CV%)
LQC
HQC

0.40 (8.61%)
0.39 (4.74%)

0.94 (5.83%)
0.51 (6.06%)

Linearity range (µg/mL)
Regression equation
Correlation coefficient (r)

0.57 – 114.74
y = 0.422 126 × x − 0.226 519
0.993 176

0.09 – 18.85
y = 3.16 888 × x − 0.146 839
0.996 044

Stability

CV%

RSE%

CV%

RSE%

Shor-term (25 °C, 6 h)

LQC

(n = 3) 4.03

− 6.26

(n = 4) 3.51

− 3.71

HQC

(n = 4) 3.78

− 10.14

(n = 4) 2.60

− 7.58

Post-processing (12 °C, 10 h)

LQC

(n = 3) 3.00

− 12.65

(n = 3) 5.73

− 5.77

HQC

(n = 4) 6.81

5.84

(n = 5) 2.03

2.36

Freeze/thaw cycles (25 °C, 6 h)

LQC

(n = 5) 1.52

4.59

(n = 5) 4.09

− 5.30

HQC

(n = 5) 3.03

10.82

(n = 5) 4.37

− 6.26

Precision and accuracy

CV%

RSE%

CV%

RSE%

Intra-assay

LLQC

(n = 7) 2.61

− 0.20

(n = 7) 5.02

3.34

LQC

(n = 7) 3.53

8.57

(n = 7) 5.17

− 5.60

MQC

(n = 7) 6.30

4.81

(n = 7) 3.29

− 4.89

HCQ

(n = 7) 4.05

− 4.24

(n = 7) 2.27

− 2.53

Inter-assays (3 assays)

LLQC

(n = 22) 8.57

0.10

(n = 22) 5.98

8.80

LQC

(n = 17) 9.61

− 1.46

(n = 20) 6.45

− 1.06

MQC

(n = 22) 6.48

0.47

(n = 22) 7.07

− 2.24

HCQ

(n = 19) 7.30

3.69

(n = 21) 3.20

− 5.01

Both ent-polyalthic and dihydro-ent-agathic acid pharmacokinetics were
characterized as a bicompartmental structural model with first-order absorption
and elimination. Plasma concentrations versus time curves of ent-polyalthic and
dihydro-ent-agathic acids are presented in [Fig. 4]. The typical values of the
parameters and interindividual variability (IIV) are presented in [Table 2] (θ i
= θ TV × eη , where θ i is the parameter value of an individual animal, θ TV is
the population parameter typical value, and η is a random variable with mean
zero and variance ω 2).

Fig. 4 Observed plasma concentrations over time of ent-polyalthic acid and
dihydro-ent-agathic acids in 44 Wistar rats following a 200-mg/kg Copaifera
duckei oil resin dose administrated by gavage (91.79 mg/kg of ent-polyalthic
acid and 18.08 mg/kg of dihydro-ent-agathic acid).
Table 2 Estimates of the population pharmacokinetic model of ent-polyalthic acid
and dihydro-ent-agathic acid in rats following oral administration (gavage) of a
200-mg/kg dose of Copaifera duckei oleoresin (91.79 mg/kg of ent-polyalthic acid
and 18.08 mg/kg of dihydro-ent-agathic acid).

Table 2 Estimates of the population pharmacokinetic model of ent-polyalthic acid
and dihydro-ent-agathic acid in rats following oral administration (gavage) of a
200-mg/kg dose of Copaifera duckei oleoresin (91.79 mg/kg of ent-polyalthic acid
and 18.08 mg/kg of dihydro-ent-agathic acid).

Parameter

ent-Polyalthic acid

Dihydro-ent-agathic acid

Estimates

Bootstrap (n = 1000)

Estimates

Bootstrap (n = 1000)

Typical value (θ)
RSE

IIV (ω 2)
RSE

Typical value median
PI (2.5 – 97.5%)

IIV median
PI (2.5 – 97.5%)

Typical value (θ)
RSE

IIV (ω 2)
RSE

Typical value median
PI (2.5 – 97.5%)

IIV median
PI (2.5 – 97.5%)

CL/F: apparent clearance. Vc/F: apparent central volume of distribution; Q:
intercompartmental clearance; Vp/F: apparent peripheral volume of distribution;
IIV: interindividual variability. RSE%: residual standard error; PI: percentile
interval range; SD: standard deviation. Cmax: maximum concentration. Tmax: time
to achieve Cmax. t 1/2: half-life. Relative F: relative bioavailability between
ent-polyalthic/dihydro-ent-agathic acids

Ka
(h−1)

0.47
12.16%

–

0.47
(0.37 – 0.90)

–

0.28
12.9%

–

0.28
(0.22 – 0.67)

–

CL/F
(L/h)

0.15
13.91%

0.25
44.68%

0.15
(0.099 – 0.19)

0.26
(0.05 – 0.75)

0.04
9.3%

0.329
26.1%

0.04
(0.03 – 0.05)

0.31
(0.16 – 0.54)

Vc/F
(L)

0.04
20.17%

–

0.04
(0.03 – 0.09)

–

0.01
27.6%

0.01
(0.01 – 0.04)

Q/F
(L/h)

0.13
11.91%

–

0.14
(0.10 – 0.21)

–

0.02
30.1%

0.02
(0.01 – 0.05)

Vp/F
(L)

2.48
30.36%

0.98
37.09%

2.50
(1.33 – 4.66)

0.98
(0.26 – 2.05)

0.18
14.0%

–

0.19
(0.14 – 0.31)

–

σ 2

0.15
21.26%

–

0.14
(0.09 – 0.20)

–

0.17
15.6%

–

0.16
(0.11 – 0.22)

–

Median
PI (25 – 75%)

Mean
(SD)

Median
PI (25 – 75%)

Mean
(SD)

Tmax
(h)

0.50
(0.45 – 0.75)

0.64
(0.36)

0.75
(0.50 – 1.50)

1.26
(0.87)

Cmax
(µg/mL)

41.63
(33.25 – 50.91)

42.75
(13.22)

22.65
(16.97 – 29.36)

22.03
(9.80)

t 1/2
(h)

11.60
(7.85 – 15.15)

11.60
(7.14)

3.49
(2.52 – 4.78)

3.49
(2.17)

AUC0–48
(μg · h/mL)

130.74
(96.43 – 176.64)

144.89
(131.16)

103.00
(69.84 – 150.67)

118.76
(68.62)

Relative F

0.245

The residual variability of both acids was described by a proportional residual
error model. Therefore, the concentration estimates of each time (j) and animal
(i) was

Yij = F ij + F ij × εij

where Yij is the observed concentration, Fij is the concentration estimate, and
ε ij is a random variable with mean zero and variance σ 2 ([Table 2]).

The goodness of fit plot (GOF) and visual predictive check (VPC) of
ent-polyaltic and dihydro-ent-agatic acids ([Figs. 5] and [6]) indicated a good
fit of the predicted plasma concentrations to the observed data, and the
bootstraps ([Table 2]) indicate acceptable bias and good accuracy of the fixed
and random effects estimates. In addition, the bootstrap had only 11.1%
minimization failures.

Fig. 5 Goodness of fit plot of ent-polyaltic and dihydro-ent-agatic acids.
Observed concentrations over population and individual predictions (left).
Conditional weighted residuals (CWRES) over population predictions and time
(right). Red line: trend line; dashed lines: identity line and two and half
times the identity (left plots); 2, 0, and − 2 CWRES (right plots).
Fig. 6 Visual predictive check (VPC) of ent-polyaltic and dihydro-ent-agatic
acids in rat plasma over time. Dots: observed plasma concentrations. Lines: 5th,
50th, and 95th percentiles of observed concentrations. Shaded areas: 5th, 50th,
and 95th percentiles of the simulated concentrations (n = 1000).

The influence of animal weight and age on the pharmacokinetic parameters of
ent-polyaltic and dihydro-ent-agatic acids were explored however due to the
uniformity of weight and age values among the animals no effect was identified.

To our knowledge, this is the first method for analyzing ent-polyaltic and
dihydro-ent-agatic acids in the plasma of rats by LC-MS/MS. The method presented
a wide linearity range and low lower limit of quantification (LLOQ)
(0.57 – 114.74 and 0.09 – 18.85 µg/mL plasma, respectively), which makes it
suitable to be applied to preclinical pharmacokinetic studies.

We could not analyze the ent-polyalthic and dihydro-ent-agathic acids by
multiple reactions monitoring (MRM). Despite several fragmentation tests with
different ionization energies and argon flux, their ionized molecules did not
generate fragment ions appreciably. A similar difficulty was also described by
Gasparetto et al. [10] in the analysis of kaurenoic acid, a diterpene contained
in Guaco.

The sample preparation method did not present a significant matrix effect for
standard or lipemic plasma samples ([Table 1]). However, the matrix effect for
hemolyzed plasma was higher than 15%, and the hemolyzed plasma samples should be
disregarded.

The method is selective for ent-polyalthic and dihydro-ent-agathic acids at
concentrations ≥ the LLQC. The chromatogramsʼ peak areas of interferents were
lower than 20% compared to the chromatogramsʼ peak analytes at LLQC
concentrations ([Fig. 3]).

The analytical method showed good intra- and inter-assay precision and accuracy,
with the coefficient of variation (CV) and relative standard error (RSE) of
quality controls lower than 15%. Similarly, the stability of the freeze/thaw
cycles, post-processing in an auto-injector, and short-term on a bench had a CV
and RSE lower than 15%.

The C. duckei oleoresin sample was prepared at 20 mg/mL in saline with Cremophor
10% to furnish a homogeneous suspension able to provide the dose of 200 mg of
oleoresin per kilogram of rat in a volume not exceeding 10 mL/kg of rat, as
described by the Good Practices for the Administration of Substances and Blood
Collection [11]. Blood samples in volumes lower than 400 µL were collected from
the caudal vein, not exceeding three samples per animal. The volume collected
was less than 10% of the animalʼs total blood volume, making volume replacement
unnecessary, according to the Good Practice Guide for the Administration of
Blood Substances and Collections, which would cause changes in pharmacokinetic
parameters [11].

This is the first report on the population pharmacokinetics of ent-polyalthic
and dihydro-ent-agathic acids. With few reports on the bioavailability of
natural products and limited population pharmacokinetic studies on natural
products, finding similar data for comparison is difficult.

ent-Polyalthic and dihydro-ent-agathic acids have similar lipophilicity
(logP = 4.9 and 4.7, respectively) and polar surface area (50.4 and 74.6 Å2,
respectively) [12]. However, the apparent clearance (CL/F), central apparent
volume of distribution (Vc/F), and peripheral apparent volume of distribution
(Vp/F) of ent-polyalthic acid are approximately 3.75-, 4.00-, and 13.78-folds
higher than the dihydro-ent-agathic ones, and the relative bioavailability
between ent-polyalthic and dihydro-ent-agathic acids is 0.245 ([Table 2]).

Due to the Brazilian populationʼs extensive use of copaibaʼs oleoresin, further
studies are needed to establish safe and effective doses for humans. Furtado et
al. [13] reported no genotoxic activity at doses up to 2000 mg of oleoresin/kg
of animal for six different Copaifera species (C. duckei, Copaifera multijuga,
Copaifera paupera, Copaifera pubiflora, Copaifera reticulata, and Copaifera
trapezifolia). However, they observed cytotoxic activity of C. duckei oleoresin
on Chinese hamster fibroblast cells at a concentration of 9.8 µg/mL.
Castro-e-Silva et al. [14] reported the oral treatment of rats with 600 mg
oleoresin/kg/day for 7 days and after partial hepatectomy. They also observed a
decrease in hepatocellular proliferation and mitochondrial breathing in the
liver. Noteworthy is that in the present study, the C. duckei oleoresin sample
was prepared at 20 mg/mL in saline with Cremophor 10% to furnish a homogeneous
suspension able to provide the dose of 200 mg of oleoresin per kilogram of rat
in a volume not exceeding 10 mL/kg of rat, as described by the Good Practices
for the Administration of Substances and Blood Collection.

Finally, it is possible to conclude that the developed LC-MS/MS analytical
method is reliable for the pharmacokinetic studies of Copaifera oleoresin
ent-polyalthic and dihydro-ent-agathic acid diterpenes. The CL/F, Vc/F, and Vp/F
of ent-polyalthic acid are higher than that of dihydro-ent-agathic. It is also
essential to observe that the literature reports that diterpenes with an
oxidized furan ring, such as teucrin A, are known liver toxic compounds [15].
All these facts indicate the need for further toxicological and clinical studies
to better understand the safety aspects of using Copaifera oleoresin.

MATERIAL AND METHODS

PLANT MATERIALS AND CHEMICALS

C. duckei Dwyer oleoresin was collected in Belém (Pará State, Brazil) at
coordinates S01°06.933′, O48°19.781′. A voucher specimen (NID:96/2012) was
obtained and deposited in the Herbarium of the Brazilian Agricultural Research
Corporation (Embrapa Eastern Amazon). The Botanist Silvane Tavares Rodrigues
identified the specimen (voucher number 175 206). ent-Polyalthic acid and
dihydro-ent-agathic acid ([Fig. 1]) were isolated and identified through nuclear
magnetic resonance analysis by our research group from the same oleoresin used
in this study [6], [16]. Their purity was also evaluated by integrating the area
under the signals corresponding to the compounds of interest in the 1H NMR
spectrum.

The IS was warfarin sodium, purchased from FURP. The following HPLC grade
reagents were used: Milli Q Plus purified water (Millipore), methanol (Merck),
acetonitrile (Sigma-Aldrich), methyl tert-butyl ether (Fischer Scientific), and
isopropanol (J. T. Baker). Formic acid and glacial acetic acid (J. T. Baker),
both of analytical grade, were employed as mobile phase modifiers.

DEVELOPMENT AND VALIDATION OF AN ANALYTICAL METHOD FOR ENT-POLYALTHIC ACID AND
DIHYDRO-ENT-AGATHIC ACID IN RAT PLASMA

LC-MS/MS ANALYSIS

Chromatographic analysis was conducted using an Alliance e2695 Waters system
(Waters Corp.). A LiChrospher 100 CN (5 µm) column with a LiChroCART 125 – 4 mm
(Merck) pre-column was utilized and maintained at a temperature of 27 °C. The
mobile phase consisted of a mixture of water, acetonitrile, isopropanol, and
formic acid (64.8 : 20 : 15 : 0.2 v/v/v/v) with a 0.7 mL/min flow rate. Mass
spectrometry detection was performed using a Quattro Micro Liquid Chromatograph
triple quadrupole (Micromass) equipped with an electrospray ionization (ESI)
source. The ent-polyalthic acid and dihydro-ent-agathic acid were detected in
the single ion recording (SIR) mode, while warfarin (IS) was detected in the MRM
mode. The ESI source was set to the negative mode. The parameters were
configured as follows: capillary voltage − 3.00 kV, source and desolvation
temperatures of 125 and 400 °C, respectively, cone and desolvation gas flow (N2)
were set at 50 and 800 L/h, respectively, and argon was employed as the
collision gas at a rate of 0.15 mL/min. The cone voltage, collision energies,
and ion transitions for each analyte were optimized according to [Table 3]. Data
acquisition and sample quantifications were performed using MassLynx 4.1 version
(Waters).

Table 3 Precusor/product ion pairs and parameters for multiple reactions
monitoring of ent-polyalthic acid, dihydro-ent-agathic acid, and the internal
standard (IS) warfarin.

Compound

Retention time (min)

MS mode

Transitions
(precursor > product)

Cone voltage (V)

Collision energy (eV)

ent-Polyalthic acid

11.18

SIR

315

Dihydro-ent-agathic acid

5.72

SIR

335

5.06

MRM

307.1 > 161.5

#
#

PREPARATION OF STANDARD SOLUTIONS

Stock solutions of ent-polyalthic (5 mg/mL) acid, dihydro-ent-agathic acid
(1 mg/mL), and warfarin sodium (IS, 5 mg/mL) were prepared separately in
methanol and kept at − 20 °C. The calibration standards were prepared by
successive dilutions in methanol to obtain concentrations of 1.15, 2.29, 3.44,
4.59, 6.88, 9.18, 22.95, 45.90, 91.79, 114.74, 137.69, 183.58, and 229.48 µg of
ent-polyalthic acid/mL methanol and 0.19, 0.38, 0.57, 0.75, 1.13, 1.51, 3.77,
7.54, 15.08, 18.85, 22.62, 30.16 e 37.70 µg of dihydro-ent-agathic acid/mL
methanol. Warfarin sodium (IS) solution was further diluted in methanol to
obtain a 5 µg/mL concentration.

SAMPLE PREPARATION

Fifty microliters of plasma sample (or blank plasma for calibration curves) were
added to 2000 µL microtubes (Axygen Scientific) to begin the sample preparation.
Subsequently, 25 µL of IS solution (5 µg/mL), 50 µL of 0.75 M acetic acid, and
25 µL of methanol (or 25 µL of each standard solution for calibration curves)
were added. The microtubes were then vortexed for 30 s using a vortex mixer
(Phoenix Luferco, model AP56). After mixing, 500 µL of the extraction solution
(methyl tert-butyl ether : isopropanol, 4 : 1 v/v) were added to the microtubes.
Another 30-s vortex mixing was performed, followed by centrifugation for 10 min
at 21 500 g, 4 °C (Himac CF8DL). The resulting supernatants were carefully
transferred to other clean microtubes and subjected to evaporation until dryness
using a vacuum concentrator. The dried residues were then reconstituted in
100 µL of the mobile phase and mixed for 30 s. The processed samples were stored
in the automatic injector at 12 °C, and 60 µL of each sample were injected into
the LC-MS/MS system. For the construction of calibration curves, peak area
ratios (analyte/IS) were plotted against plasma concentrations. The
concentration ranges were 0.57 to 114.74 µg/mL and 0.09 to 18.85 µg/mL for
ent-polyalthic acid and dihydro-ent-agathic acid, respectively.

METHOD VALIDATION

The analytical method was validated according to FDA and EMA guidelines [17].
The quality control samples were prepared at the plasma concentrations shown in
[Table 4].

Table 4 Quality control concentrations of ent-polyalthic and dihydro-ent-agathic
acids in rat plasma.

Quality control sample

ent-Polyalthic acid (µg/mL)

Dihydro-ent-agathic acid (µg/mL)

LLQC: lower limit concentrations quality control, LQC: lower concentration
quality control, MQC: medium concentration quality control, HQC: higher quality
control concentrations, DQC: dilution quality control

LLQC

0.57

0.09

LQC

1.72

0.28

MQC

57.37

9.42

HQC

91.79

15.08

DQC

114.74

18.85

The matrix effect was assessed using eight 50 µL aliquots of blank plasma
obtained from different rats, including two lipemic samples, two hemolyzed
samples, and four standard samples. The blank plasma extracts were then spiked
with standard solutions at concentrations corresponding to the high-quality
control (HQC) and low-quality control (LQC), along with the addition of the IS
solution. Additionally, exact standard solutions in methanol spiked with the IS
solution were analyzed. The matrix factor normalized with the IS (NMF) was
calculated by dividing the peak area ratios of analyte/IS from the
post-extracted plasma samples by the peak area ratios of analyte/IS from the
neat solutions. The matrix effect was determined by calculating the CV of all
obtained MFs.

Selectivity was evaluated using blank plasma from eight different sources,
including four standard samples, two lipemic samples, and two hemolyzed samples.
The resulting chromatograms were compared to LLQC concentration samples.

Linearity was assessed through triplicate calibration curves, including a blank
and zero samples. The carryover effect was evaluated by consecutively injecting
three blank samples, followed by injecting the sample at the HQC concentration.

Precision and accuracy (intraday and inter-day) were evaluated by performing
seven replicates of LLQC, LQC, medium quality control (MQC), and HQC of
ent-polyalthic and dihydro-ent-agathic acids in a single analytical run
(intra-assay) and in three different analytical runs (inter-assay). The
precision and accuracy results are expressed as the CV and RSE.

Stability tests in rat plasma were conducted using four replicates of LQC and
HQC samples. For the freeze/thaw stability evaluation, the LQC and HQC
replicates were subjected to three cycles of freezing at − 70 °C for 24 h,
followed by thawing at room temperature and freezing again at − 70 °C for 24 h.
The samples were then analyzed at the end of the three cycles. Short-term
stability was assessed by keeping the LQC and HQC samples at room temperature
for 1 h before preparation and analysis. Post-processing stability was evaluated
by storing the processed LQC and HQC samples in the automatic injector at 12 °C
for 24 h before analysis. The stability results are expressed as the CV and RSE.

POPULATION PHARMACOKINETICS OF ENT-POLYALTHIC ACID AND DIHYDRO-ENT-AGATHIC ACID
IN RATS

ANIMAL EXPERIMENTS

Male Wistar rats (260 ± 30 g, n = 44) were housed in metabolic cages under
controlled temperature (25 ± 1 °C), relative humidity (40 – 70%), a 12-h
light-dark cycle, and with free access to food and water. On December 9, 2015,
the Ethics Committee of Universidade de Franca (CEUA) approved the experimental
protocol on the Use of Animals under protocol number 057/15.

After 12 h fasting, 20 mg/mL C. duckei oleoresin, dissolved in physiological
saline solution with 1.0% Cremophor, were orally administered by gavage at a
dose of 200 mg/kg (91.79 mg/kg of ent-polyalthic acid and 18.08 mg/kg of
dihydro-ent-agathic acid) to a total of 44 rats. Serial blood samples of 200 µL
(3 to 4 samples per animal) were collected from tail vein at 5, 15, 30, 45 min,
and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 18, 20, 24, 30, 36, and 48 h (n = 8 for each
sampling time) after oleoresin administration and transferred to tubes
containing heparin as an anticoagulant (Liquemine 5000 IU; Roche). After
centrifugation (10 min, 9560 g, 4 °C), the plasma samples were stored at − 70 °C
until analysis.

#
#

POPULATION PHARMACOKINETIC MODELS

Population pharmacokinetics models of ent-polyalthic and dihydro-ent-agathic
acids in rats were evaluated by nonlinear mixed-effects modelling conducted in
NONMEN software, version 7.4.3 (ICON Development Solutions), with compiler GNU
Fortran 4.6 (Free Software Foundation, Inc.) and interface PsN, version 4.9.0
(Perlspeaks-NONMEM) [18]. R version 3.6.1 (R Foundation for Statistical
Computing) was used to reorganize the dataset, statistical summaries, and
graphics.

The estimations were conducted based on the first-order conditional estimation
with the interaction method (FOCE-I). The model-building criteria included (1)
successful minimization, (2) reduced relative standard error and shrinkage
values of estimates, (3) number of significant digits, (4) successful covariance
step, (5) correlation between model parameters, and (6) acceptable gradients at
the last iteration [19], [20].

All fixed and random effects were introduced into the model according to a
stepwise procedure exploring mono- or bicompartmental pharmacokinetics with
first order and elimination and different absorption models (first-order,
lag-time, or transit compartment models). The residual variability was explored
by additive, proportional, or proportional combined with additive error models.
The IIV was explored in all parameters assuming a log-normal distribution.

Comparison between hierarchical models was based on graphic and statistical
methods that included (1) reduction of the objective function value (OFV) and
AIC (Akaike information criteria), (2) values of relative standard error and
shrinkage, (3) GOF that included plots of the predicted population (PRED) and
individual (IPRED) concentrations versus the observed concentrations and the
conditional weighted residuals (CWRES) versus population predicted
concentrations and time [20], [21].

A stepwise forward inclusion/backward elimination procedure was used for
covariate selection, according to the concept that the difference in − 2 log
likelihood between two models is approximately χ2 distributed, with degrees of
freedom equal to the difference in the number of parameters between the
hierarchical models [22]. The covariates were introduced one by one and retained
if a decrease in OFV of at least 3.84 units (p < 0.05) was observed. During the
backward elimination procedure, an increase in OFV of at least 7.8 units
(p < 0.005) was used as a criterion for a significant effect.

The predictive performance of ent-polyalthic and dihydro-ent-agathic acid
pharmacokinetic models was assessed via graphical and statistical methods,
including VPCs [20], [21], [23] and bootstrapping [24], in addition to graphical
evaluation of the GOF. VPCs were obtained from 1000 simulations per animal of
the ent-polyalthic and dihydro-ent-agathic acid plasma concentrations from 0 to
48 h. Bootstrap analysis identified bias, stability, and precision of the
estimates obtained with the model and was performed with 1000 new datasets
generated by resampling individuals (with replacement) from the original
dataset.

The area under the plasma concentration from 0 to 48 h (AUC0 – 48) of ent-
polyalthic and dihydro-ent-agathic acids was calculated by the trapezoidal rule
in R version 3.6.1 from the modelʼs individual predicted concentrations over
time. Then, the relative bioavailability between
ent-polyalthic/dihydro-ent-agathic acids of each animal was accessed through the
equation:

F = AUC0 – 48 of ent-polyalthic acid × dose of dihydro-ent-agathic acid

AUC0 – 48 of dihydro-ent-agathic acid × dose of ent-polyalthic acid

#
#

CONTRIBUTORSʼ STATEMENT

Data collection: F. A. Aguila, Nardotto G. H. B., Oliveira, L. C.; design of the
study: F. A. Aguila, Bastos, J. K., Veneziani R. C. S., Nardotto G. H. B.,
Oliveira, L. C., Rocha, A., Lanchote, V. L., Ambrosio S.R; statistical analysis:
F. A. Aguila, Nardotto G. H. B., Oliveira, L. C., Rocha, A., Lanchote, V. L.,
Ambrosio S.R; analysis and interpretation of the data: F. A. Aguila, Bastos,
J. K., Veneziani R. C. S., Nardotto G. H. B., Oliveira, L. C., Rocha, A.,
Lanchote, V. L., Ambrosio S.R; drafting the manuscript: Bastos, J. K., Veneziani
R. C. S., Rocha, A., Lanchote, V. L., Ambrosio S.R; critical revision of the
manuscript: Bastos, J. K., Veneziani R. C. S., Lanchote, V. L., Ambrosio S.R,
Ambrosio S. R.

#
#

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

ACKNOWLEDGEMENTS

The authors thank the State of São Paulo Research Foundation (FAPESP) for
financial support (grant number 2011/13 630 – 7) and CAPES and CNPq for
fellowships.

* REFERENCES

* 1 Arruda C, Mejia JAA, Ribeiro VP, Borges CHG, Martins CHG, Veneziani RCS,
Ambrosio SR, Bastos JK. Occurrence, chemical composition, biological
activities and analytical methods on Copaifera genus-A review. Biomed
Pharmacother 2019; 109: 1-20
CrossrefPubMedGoogle Scholar
* 2 Cardinelli CC, Silva JEAE, Ribeiro R, Veiga VF, dos Santos EP, de Freitas
ZMF. Toxicological effects of copaiba oil (Copaifera spp.) and its active
components. Plants (Basel) 2023; 12: e1054
PubMedGoogle Scholar
* 3 Veiga VF, Pinto AC. The Copaifera L. genus. Quim Nova 2002; 25: 273-286
CrossrefPubMedGoogle Scholar
* 4 Veiga VF, Zunino L, Calixto JB, Patitucci ML, Pinto AC. Phytochemical and
antioedematogenic studies of commercial copaiba oils available in Brazil.
Phytother Res 2001; 15: 476-480
CrossrefPubMedGoogle Scholar
* 5 Carneiro LJ, Tasso TO, Santos MFC, Goulart MO, dos Santos R, Bastos JK, da
Silva JJM, Crotti AEM, Parreira RLT, Orenha RP, Veneziani RCS, Ambrosio SR.
Copaifera multijuga, Copaifera pubiflora and Copaifera trapezifolia
oleoresins: Chemical characterization and in vitro cytotoxic potential
against tumoral cell lines. J Brazil Chem Soc 2020; 31: 1679-1689
PubMedGoogle Scholar
* 6 Carneiro LJ, Bianchi TC, da Silva JJM, Oliveira LC, Borges CHG, Lemes DC,
Bastos JK, Veneziani RCS, Ambrosio SR. Development and validation of a rapid
and reliable RP-HPLC-PDA method for the quantification of six diterpenes in
Copaifera duckei, Copaifera reticulata and Copaifera multijuga oleoresins. J
Brazil Chem Soc 2018; 29: 729-737
PubMedGoogle Scholar
* 7 da Silva JJM, Crevelin EJ, Carneiro LJ, Rogez H, Veneziani RCS, Ambrósio
SR, Beraldo Moraes LA, Bastos JK. Development of a validated
ultra-high-performance liquid chromatography tandem mass spectrometry method
for determination of acid diterpenes in Copaifera oleoresins. J Chromatogr A
2017; 1515: 81-90
CrossrefPubMedGoogle Scholar
* 8 da Trindade R, da Silva JK, Setzer WN. Copaifera of the neotropics: A
review of the phytochemistry and pharmacology. Int J Mol Sci 2018; 19: 1511
CrossrefPubMedGoogle Scholar
* 9 Sachetti CG, de Carvalho RR, Paumgartten FJR, Lameira OA, Caldas ED.
Developmental toxicity of copaiba tree (Copaifera reticulata Ducke, Fabaceae)
oleoresin in rat. Food Chem Toxicol 2011; 49: 1080-1085
CrossrefPubMedGoogle Scholar
* 10 Gasparetto J, Peccinini R, de Francisco T, Cerqueira L, Campos F,
Pontarolo R. A kinetic study of the main guaco metabolites using syrup
formulation and the identification of an alternative route of coumarin
metabolism in humans. PLoS One 2015; 10: e0118922
CrossrefPubMedGoogle Scholar
* 11 Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal
JM, van de Vorstenbosch C. A good practice guide to the administration of
substances and removal of blood, including routes and volumes. J Appl Toxicol
2001; 21: 15-23
CrossrefPubMedGoogle Scholar
* 12 Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules. Sci Rep 2017; 7: 1-13
CrossrefPubMedGoogle Scholar
* 13 Furtado RA, de Oliveira PF, Senedese JM, Ozelin SD, de Souza LDR, Leandro
LF, de Oliveira WL, da Silva JJM, Oliveira LC, Rogez H, Ambrósio SR,
Veneziani RCS, Bastos JK, Tavares DC. Assessment of toxicogenetic activity of
oleoresins and leaves extracts of six Copaifera species for prediction of
potential human risks. J Ethnopharmacol 2018; 221: 119-125
CrossrefPubMedGoogle Scholar
* 14 Castro-E-Silva jr. O, Zucoloto S, Ramalho FS, Ramalho LNZ, Reis JMC,
Bastos AAC, Brito MVH. Antiproliferative activity of Copaifera duckei
oleoresin on liver regeneration in rats. Phytother Res 2004; 18: 92-94
CrossrefPubMedGoogle Scholar
* 15 Kouzi SA, Mcmurtry RJ, Nelson SD. Hepatotoxicity of germander (Teucrium
chamaedrys L.) and one of its constituent neoclerodane diterpenes teucrin A
in the mouse. Chem Res Toxicol 1994; 7: 850-856
CrossrefPubMedGoogle Scholar
* 16 Borges CHG, Cruz MG, Carneiro LJ, da Silva JJM, Bastos JK, Tavares DC, de
Oliveira PF, Rodrigues V, Veneziani RCS, Parreira RLT, Caramori GF, Nagurniak
GR, Magalhães LG, Ambrósio SR. Copaifera duckei oleoresin and its main
nonvolatile terpenes: In vitro schistosomicidal properties. Chem Biodivers
2016; 13: 1348-1356
CrossrefPubMedGoogle Scholar
* 17 EMEA/CHMP/EWP. Guideline on bioanalytical method validation, Guideline
Rev. 1 Corr. 2, (07/21 2011).
https://www.ema.europa.eu/en/bioanalytical-method-validation Accessed: 02/13
2020
PubMedGoogle Scholar
* 18 Bauer RJ. NONMEM tutorial part I: Description of commands and options,
with simple examples of population analysis. CPT Pharmacometrics Syst
Pharmacol 2019; 8: 525-537
CrossrefPubMedGoogle Scholar
* 19 Bauer RJ. NONMEM tutorial part II: Estimation methods and advanced
examples. CPT Pharmacometrics Syst Pharmacol 2019; 8: 538-556
CrossrefPubMedGoogle Scholar
* 20 Mould DR, Upton RN. Basic concepts in population modeling, simulation, and
model-based drug development-part 2: Introduction to pharmacokinetic modeling
methods. CPT Pharmacometrics Syst Pharmacol 2013; 2: e38
CrossrefPubMedGoogle Scholar
* 21 Nguyen THT, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC,
John J, Karlsson MO, Mould DR, Ruixo JJP, Plan EL, Savic R, van Hasselt JGC,
Weber B, Zhou C, Comets E, Mentre F. Model evaluation of continuous data
pharmacometric models: Metrics and graphics. CPT Pharmacometrics Syst
Pharmacol 2017; 6: 87-109
CrossrefPubMedGoogle Scholar
* 22 Maitre PO, Buhrer M, Thomson D, Stanski DR. A three-step approach
combining Bayesian regression and NONMEM population analysis: Application to
midazolam. J Pharmacokinet Biopharm 1991; 19: 377-384
CrossrefPubMedGoogle Scholar
* 23 Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected
visual predictive checks for diagnosing nonlinear mixed-effects models. Aaps
J 2011; 13: 143-151
CrossrefPubMedGoogle Scholar
* 24 Dowd PA, Pardo-Iguzquiza E, Egozcue JJ. The total bootstrap median: A
robust and efficient estimator of location and scale for small samples. J
Appl Stat 2015; 42: 1306-1321
CrossrefPubMedGoogle Scholar

CORRESPONDENCE

Profa. Dra. Vera Lucia Lanchote
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas
School of Pharmaceutical Sciences of Ribeirão Preto
University of São Paulo
Av. do Café, s/n – Vila Monte Alegre
14040-900 Ribeirão Preto – SP
Brazil
Telefon: + 55 16 33 15 46 99
eMail: lanchote@fcfrp.usp.br

Prof. Dr. Sérgio Ricardo Ambrósio
Núcleo de Pesquisa em Ciências Exatas e Tecnológicas
University of Franca
Av. Dr. Armando Sales Oliveira, 201 – Parque Universitário
14404-600 Franca – SP
Brazil
Telefon: + 55 16 37 11 88 88
eMail: sergio.ambrosio@unifran.edu.br

PUBLIKATIONSVERLAUF

Eingereicht: 22. November 2023

Angenommen nach Revision: 15. Mai 2024

Accepted Manuscript online:
15. Mai 2024

Artikel online veröffentlicht:
18. Juni 2024

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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* REFERENCES

Lizenzen und Reprints
Fig. 1 Chemical structures of the major nonvolatile constituents of Copaifera
duckei oil resin: ent-polyalthic acid (1) and dihydro-ent-agathic acid (2).
Fig. 2 Full scan mass spectrum of Copaifera duckei oil resin,
dihydro-ent-agathic, ent-polyalthic acids, and warfarin sodium (internal
standard) diluted in the mobile phase. Fig. 3 Chromatograms of the lower limit
quality control (LLQC), low-quality control (LQC), and high-quality control
(HQC) samples and of blank plasma samples immediately following HQC sample
analysis of ent-polyalthic and dihydro-ent-agathic acids. Fig. 4 Observed plasma
concentrations over time of ent-polyalthic acid and dihydro-ent-agathic acids in
44 Wistar rats following a 200-mg/kg Copaifera duckei oil resin dose
administrated by gavage (91.79 mg/kg of ent-polyalthic acid and 18.08 mg/kg of
dihydro-ent-agathic acid). Fig. 5 Goodness of fit plot of ent-polyaltic and
dihydro-ent-agatic acids. Observed concentrations over population and individual
predictions (left). Conditional weighted residuals (CWRES) over population
predictions and time (right). Red line: trend line; dashed lines: identity line
and two and half times the identity (left plots); 2, 0, and − 2 CWRES (right
plots). Fig. 6 Visual predictive check (VPC) of ent-polyaltic and
dihydro-ent-agatic acids in rat plasma over time. Dots: observed plasma
concentrations. Lines: 5th, 50th, and 95th percentiles of observed
concentrations. Shaded areas: 5th, 50th, and 95th percentiles of the simulated
concentrations (n = 1000).

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* VERWENDUNG REDUZIERTER DATEN ZUR AUSWAHL VON WERBEANZEIGEN 613 LIEFERANTEN
KÖNNEN DIESEN ZWECK NUTZEN

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Werbeanzeigen, die Ihnen auf diesem Dienst präsentiert werden, können auf
reduzierten Daten basieren, wie z. B. der Webseite oder App, die Sie gerade
verwenden, Ihrem ungefähren Standort, Ihrem Gerätetyp oder den Inhalten, mit
denen Sie interagieren (oder interagiert haben) (z. B., um die
Anzeigefrequenz der Werbung zu begrenzen, die Ihnen ausgespielt werden).

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Den Berechtigten Interessen Widersprechen Widerspruch entfernen

* ERSTELLUNG VON PROFILEN FÜR PERSONALISIERTE WERBUNG 496 LIEFERANTEN KÖNNEN
DIESEN ZWECK NUTZEN

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Informationen über Ihre Aktivitäten auf diesem Dienst (wie ausgefüllte
Formulare, angesehene Inhalte) können gespeichert und mit anderen
Informationen über Sie (z. B. Informationen aus Ihrer vorherigen Aktivität
auf diesem Dienst oder anderen Webseiten oder Apps) oder ähnlichen Benutzern
kombiniert werden. Diese werden dann verwendet, um ein Profil über Sie zu
erstellen oder zu verbessern (dies kann z. B. mögliche Interessen und
persönliche Merkmale beinhalten). Ihr Profil kann (auch zu einem späteren
Zeitpunkt) verwendet werden, um es zu ermöglichen, Ihnen Werbung zu
präsentieren, die aufgrund Ihrer möglichen Interessen für Sie wahrscheinlich
relevanter ist.

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* VERWENDUNG VON PROFILEN ZUR AUSWAHL PERSONALISIERTER WERBUNG 492 LIEFERANTEN
KÖNNEN DIESEN ZWECK NUTZEN

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Werbung, die Ihnen auf diesem Dienst angezeigt wird, kann auf Ihrem
Werbeprofil basieren. Dieses Werbeprofil kann Ihre Aktivitäten (wie
ausgefüllte Formulare, angesehene Inhalte) auf diesem Dienst oder anderen
Webseiten oder Apps, mögliche Interessen und persönliche Merkmale beinhalten.

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* ERSTELLUNG VON PROFILEN ZUR PERSONALISIERUNG VON INHALTEN 220 LIEFERANTEN
KÖNNEN DIESEN ZWECK NUTZEN

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Informationen über Ihre Aktivitäten auf diesem Dienst (wie zum Beispiel:
ausgefüllte Formulare, angesehene nicht werbliche Inhalte) können gespeichert
und mit anderen Informationen über Sie (wie Ihrer vorherigen Aktivität auf
diesem Dienst oder anderen Webseiten oder Apps) oder ähnlichen Benutzern
kombiniert werden. Diese werden dann verwendet, um ein Profil über Sie zu
erstellen oder zu ergänzen (dies kann z.B. mögliche Interessen und
persönliche Merkmale beinhalten). Ihr Profil kann (auch zu einem späteren
Zeitpunkt) verwendet werden, um Ihnen Inhalte anzuzeigen, die aufgrund Ihrer
möglichen Interessen für Sie wahrscheinlich relevanter sind, indem z. B. die
Reihenfolge, in der Ihnen Inhalte angezeigt werden, geändert wird, um es
Ihnen noch leichter zu machen, Inhalte zu finden, die Ihren Interessen
entsprechen.

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* VERWENDUNG VON PROFILEN ZUR AUSWAHL PERSONALISIERTER INHALTE 193 LIEFERANTEN
KÖNNEN DIESEN ZWECK NUTZEN

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Inhalte, die Ihnen auf diesem Dienst präsentiert werden, können auf Ihren
Inhaltsprofilen basieren, die Ihre Aktivitäten auf diesem oder anderen
Diensten (wie Formulare, die Sie einreichen, Inhalte, die Sie sich ansehen),
mögliche Interessen und persönliche Aspekte widerspiegeln können. Dies kann
beispielsweise dazu genutzt werden, um die Reihenfolge anzupassen, in der
Ihnen Inhalte angezeigt werden, um es Ihnen noch leichter zu machen,
(Nicht-Werbe-)Inhalte zu finden, die Ihren Interessen entsprechen.

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* MESSUNG DER WERBELEISTUNG 715 LIEFERANTEN KÖNNEN DIESEN ZWECK NUTZEN

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Informationen darüber, welche Werbung Ihnen präsentiert wird und wie Sie
damit interagieren, können verwendet werden, um festzustellen, wie sehr eine
Werbung Sie oder andere Benutzer angesprochen hat und ob die Ziele der
Werbekampagne erreicht wurden. Die Informationen umfassen zum Beispiel, ob
Sie sich eine Anzeige angesehen haben, ob Sie daraufgeklickt haben, ob sie
Sie dazu animiert hat, ein Produkt zu kaufen oder eine Webseite zu besuchen
usw. Diese Informationen sind hilfreich, um die Relevanz von Werbekampagnen
zu ermitteln.

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Den Berechtigten Interessen Widersprechen Widerspruch entfernen

* MESSUNG DER PERFORMANCE VON INHALTEN 361 LIEFERANTEN KÖNNEN DIESEN ZWECK
NUTZEN

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Informationen darüber, welche Werbung Ihnen präsentiert wird und wie Sie
damit interagieren, können dazu verwendet werden festzustellen, ob (nicht
werbliche) Inhalte z. B. die beabsichtigte Zielgruppe erreicht und Ihren
Interessen entsprochen haben. Dazu gehören beispielsweise Informationen
darüber, ob Sie einen bestimmten Artikel gelesen, sich ein bestimmtes Video
angesehen, einen bestimmten Podcast angehört oder sich eine bestimmte
Produktbeschreibung angesehen haben, wie viel Zeit Sie auf diesem Dienst und
den von Ihnen besuchten Webseiten verbracht haben usw. Diese Informationen
helfen dabei, die Relevanz von (nicht werblichen) Inhalten, die Ihnen
angezeigt werden, zu ermitteln.

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Den Berechtigten Interessen Widersprechen Widerspruch entfernen

* ANALYSE VON ZIELGRUPPEN DURCH STATISTIKEN ODER KOMBINATIONEN VON DATEN AUS
VERSCHIEDENEN QUELLEN 454 LIEFERANTEN KÖNNEN DIESEN ZWECK NUTZEN

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Basierend auf der Kombination von Datensätzen (wie Benutzerprofilen,
Statistiken, Marktforschung, Analysedaten) können Berichte über Ihre
Interaktionen und die anderer Benutzer mit Werbe- oder (nicht werblichen)
Inhalten erstellt werden, um gemeinsame Merkmale zu ermitteln (z. B., um
festzustellen, welche Zielgruppen für eine Werbekampagne oder für bestimmte
Inhalte empfänglich sind).

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Den Berechtigten Interessen Widersprechen Widerspruch entfernen

* ENTWICKLUNG UND VERBESSERUNG DER ANGEBOTE 538 LIEFERANTEN KÖNNEN DIESEN ZWECK
NUTZEN

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Informationen über Ihre Aktivitäten auf diesem Angebot, wie z. B. Ihre
Interaktion mit Anzeigen oder Inhalten, können dabei helfen, Produkte und
Angebote zu verbessern und neue Produkte und Angebote zu entwickeln basierend
auf Benutzerinteraktionen, der Art der Zielgruppe usw. Dieser
Verarbeitungszweck umfasst nicht die Entwicklung, Ergänzung oder Verbesserung
von Benutzerprofilen und Kennungen.

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Den Berechtigten Interessen Widersprechen Widerspruch entfernen

* VERWENDUNG REDUZIERTER DATEN ZUR AUSWAHL VON INHALTEN 127 LIEFERANTEN KÖNNEN
DIESEN ZWECK NUTZEN

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Inhalte, die Ihnen auf diesem Dienst präsentiert werden, können auf
reduzierten Daten basieren, wie z. B. der Webseite oder App, die Sie
verwenden, Ihrem ungefähren Standort, Ihrem Endgerätetyp oder der
Information, mit welchen Inhalten Sie interagieren (oder interagiert haben)
(z. B. zur Begrenzung wie häufig Ihnen ein Video oder ein Artikel angezeigt
wird).

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Den Berechtigten Interessen Widersprechen Widerspruch entfernen

Liste von IAB-Lieferanten‎

VERWENDUNG GENAUER STANDORTDATEN 258 PARTNER KÖNNEN DIESE SONDERFUNKTION NUTZEN

Verwendung genauer Standortdaten

Mit Ihrer Zustimmung kann Ihr genauer Standort (mit einem Radius von weniger als
500 Metern) zur Unterstützung der in diesem Rahmenwerk erläuterten Zwecke
verwendet werden.

Liste von IAB-Lieferanten‎

ENDGERÄTEEIGENSCHAFTEN ZUR IDENTIFIKATION AKTIV ABFRAGEN 125 PARTNER KÖNNEN
DIESE SONDERFUNKTION NUTZEN

Endgeräteeigenschaften zur Identifikation aktiv abfragen

Mit Ihrer Zustimmung können bestimmte für Ihr Endgerät spezifische Merkmale
angefordert und verwendet werden, um es von anderen Endgeräten zu unterscheiden
(wie z. B. die installierten Zeichensätze oder Plugins, die Auflösung Ihres
Bildschirms), um die in diesem Rahmenwerk erläuterten Zwecke zu unterstützen.

Liste von IAB-Lieferanten‎

GEWÄHRLEISTUNG DER SICHERHEIT, VERHINDERUNG UND AUFDECKUNG VON BETRUG UND
FEHLERBEHEBUNG 507 PARTNER KÖNNEN DIESEN SONDERZWECK NUTZEN

Immer aktiv

Ihre Daten können verwendet werden, um ungewöhnliche und potenziell
betrügerische Aktivitäten (zum Beispiel bezüglich Werbung, Werbe-Klicks durch
Bots) zu überwachen und zu verhindern, und um sicherzustellen, dass Systeme und
Prozesse ordnungsgemäß und sicher funktionieren. Die Daten können auch verwendet
werden, um Probleme zu beheben, die Sie, der Webseite- oder Appbetreiber oder
der Werbetreibende bei der Bereitstellung von Inhalten und Anzeigen und bei
Ihrer Interaktion mit diesen haben können.

Liste von IAB-Lieferanten‎ | Illustrationen anzeigen

BEREITSTELLUNG UND ANZEIGE VON WERBUNG UND INHALTEN 501 PARTNER KÖNNEN DIESEN
SONDERZWECK NUTZEN

Immer aktiv

Bestimmte Informationen (wie IP-Adresse oder Endgerätefunktionen) werden
verwendet, um die technische Kompatibilität des Inhalts oder der Werbung zu
gewährleisten und die Übertragung des Inhalts oder der Werbung auf Ihr Endgerät
zu ermöglichen.

Liste von IAB-Lieferanten‎ | Illustrationen anzeigen

ABGLEICHUNG UND KOMBINATION VON DATEN AUS UNTERSCHIEDLICHEN QUELLEN 359 PARTNER
KÖNNEN DIESE FUNKTION NUTZEN

Immer aktiv

Informationen über Ihre Aktivitäten auf diesem Dienst können zur Unterstützung
der in diesem Rahmenwerk erläuterten Zwecke mit anderen Informationen über Sie
aus unterschiedlichen Quellen abgeglichen und kombiniert werden (z. B. Ihre
Aktivitäten auf einem anderen Online-Dienst, Ihrer Nutzung einer Kundenkarte im
Geschäft oder Ihren Antworten auf eine Umfrage).

Liste von IAB-Lieferanten‎

VERKNÜPFUNG VERSCHIEDENER ENDGERÄTE 326 PARTNER KÖNNEN DIESE FUNKTION NUTZEN

Immer aktiv

Zur Unterstützung der in diesem Rahmenwerk erläuterten Zwecke kann ermittelt
werden, ob es wahrscheinlich ist, dass Ihr Endgerät mit anderen Endgeräten
verbunden ist, die Ihnen oder Ihrem Haushalt angehören (z. B., weil Sie sowohl
auf Ihrem Handy als auch auf Ihrem Computer beim gleichen Dienst angemeldet sind
oder weil Sie auf beiden Endgeräten die gleiche Internetverbindung verwenden).

Liste von IAB-Lieferanten‎

IDENTIFIKATION VON ENDGERÄTEN ANHAND AUTOMATISCH ÜBERMITTELTER INFORMATIONEN 487
PARTNER KÖNNEN DIESE FUNKTION NUTZEN

Immer aktiv

Ihr Endgerät kann zur Unterstützung der in diesem Rahmenwerk erläuterten Zwecke
mithilfe von Informationen unterschieden werden, die es beim Zugriff auf das
Internet automatisch übermittelt (z. B. die IP-Adresse Ihrer Internetverbindung
oder die Art des Browsers, den Sie verwenden).

Liste von IAB-Lieferanten‎
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