24/10/2020 [Full text] Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after in | CPAA

ORIGINAL RESEARCH

Pharmacokinetics and pharmacodynamics of

acetylsalicylic acid after intravenous and oral
administration to healthy volunteers
Authors Nagelschmitz J, Blunck M, Kraetzschmar J, Ludwig M, Wensing G, Hohlfeld

Received 10 May 2013

Accepted for publication 16 July 2013

Published 19 March 2014 Volume 2014:6 Pages 51—59

DOI https://doi.org/10.2147/CPAA.S47895

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

J Nagelschmitz,1 M Blunck,1 J Kraetzschmar,1 M Ludwig,1 G Wensing,1 T Hohlfeld2

1
Bayer HealthCare AG, Clinical Pharmacology, Wuppertal, Germany; 2Institut für Pharmakologie und Klinische
Pharmakologie, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany
Background: The pharmacology of single doses of acetylsalicylic acid (ASA) administered intravenously (250
or 500 mg) or orally (100, 300, or 500 mg) was evaluated in a randomized, placebo-controlled, crossover
study.
Methods: Blood and urine samples were collected before and up to 24 hours after administration of ASA in
22 healthy volunteers. Pharmacokinetic parameters and measurements of platelet aggregation were
determined using validated techniques.
Results: A comparison between administration routes showed that the geometric mean dose-corrected peak
concentrations (Cmax/D) and the geometric mean dose-corrected area under the curve (AUC0–∞/D) were
higher following intravenous administration of ASA 500 mg compared with oral administration (estimated
ratios were 11.23 and 2.03, respectively). Complete inhibition of platelet aggregation was achieved within 5
minutes with both intravenous ASA doses, reflecting a rapid onset of inhibition that was not observed with
oral dosing. At 5 minutes after administration, the mean reduction in arachidonic acid-induced thromboxane
B2 synthesis ex vivo was 99.3% with ASA 250 mg intravenously and 99.7% with ASA 500 mg intravenously.
In exploratory analyses, thromboxane B2 synthesis was significantly lower after intravenous versus oral ASA
500 mg (P<0.0001) at each observed time point up to the first hour after administration. Concentrations of
6-keto-prostaglandin1α at 5 and 20 minutes after dosing were also significantly lower with ASA 500 mg
intravenously than with ASA 500 mg orally.
Conclusion: This study demonstrates that intravenous ASA provides more rapid and consistent platelet
inhibition than oral ASA within the first hour after dosing.
Keywords: intravenous acetylsalicylic acid, oral acetylsalicylic acid, pharmacodynamics, pharmacokinetics,
platelet aggregation, cyclooxygenase-1, thromboxane formation

Introduction
Low doses of orally administered acetylsalicylic acid (ASA) irreversibly inhibit platelet cyclooxygenase
(COX)-1, thereby preventing the enzymatic formation of thromboxane A2, a potent activator of both platelet
aggregation and vasoconstriction. Inhibition of COX-2-dependent prostaglandins occurs at much higher oral
ASA doses than those used in cardiovascular prophylaxis. The ratio of IC50 values (the concentration
producing 50% enzyme inhibition) for inhibition of COX-2/COX-1 is 166.1 As a result, the antiplatelet and
vasodilatory effects of the COX-2-mediated metabolite, prostaglandin I2 (PGI2), should be less affected at low
doses of ASA.
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In one study in healthy volunteers, the peak plasma concentration (Cmax) following administration of soluble
ASA 600 mg/day was significantly higher than that of other oral formulations (13.82 μg/mL versus 5.51
μg/mL with plain ASA 650 mg/day orally) and the half-life (t1/2) was significantly shorter (16 minutes versus
32 minutes, respectively).7 However, this study did not include intravenous ASA, which has been shown to
have a t1/2 of 2.8 minutes and 15 minutes in the initial distribution phase and the elimination phase,
respectively.8 This indicates that intravenous ASA is rapidly converted to salicylic acid by hydrolysis and
presystemic COX acetylation. Thus intravenous administration likely offers a means of achieving rapid
inhibition of platelet function in an emergency setting. However, there are only a few studies that have
compared intravenous ASA and oral ASA, and these were performed in animal models.5,9 Human data are
even more scarce and have used doses (ASA 1 g/day intravenously or orally) that are not recommended as
atherothrombotic prophylaxis.10
The aim of this study was to compare the pharmacokinetics and pharmacodynamics of intravenously
administered ASA (D,L-lysine acetylsalicylate · glycine, 250 and 500 mg intravenously) with orally
administered ASA (100, 300, and 500 mg orally) in healthy volunteers. The intravenous doses of ASA were
chosen because previous studies have shown that ASA 250 mg intravenously reduces the rate of
thromboembolic events without increasing intraoperative bleeding.11 This dose is also close to guideline
recommendations for patients with acute coronary syndrome (ie, ASA 162–325 mg initially, reduced to 75–
162 mg daily for indefinite use),11–13 while ASA 500 mg intravenously is widely used as a loading dose in
patients with acute coronary syndrome. The 100 mg dose of ASA administered orally was also studied
because this is close to the minimum oral dose approved for the treatment of acute coronary syndrome.
Materials and methods
Subjects
A total of 22 healthy volunteers (14 males and eight postmenopausal females) aged >40 years with a body
mass index range of 20–37 kg/m2 were studied. The subjects abstained from ASA or any other medication
that could interfere with platelet function for 2 weeks prior to the study. Informed consent was obtained from
all subjects prior to inclusion.
Protocol
Each subject was randomized to receive a single dose of NaCl (placebo) solution (5 mL intravenously), ASA
(D,L-lysine acetylsalicylate · glycine) 250 mg or 500 mg intravenously, or ASA 100, 300, or 500 mg plain
tablets orally (supplied by Bayer HealthCare AG, Wuppertal, Germany) in the fasted state, according to the
randomization list (Global Biometry, Bayer HealthCare AG). Randomization was carried out after the prestudy
examination, with subjects being assigned to random numbers starting with 01 in ascending order as they
were listed, and the individual sequence of the treatments was then determined by the randomization list;
female subjects were randomized into a subgroup of eight random numbers.
For oral dosing, subjects were asked to chew the tablets and swallow them with approximately 240 mL of
water. Intravenous ASA was dissolved in 5 mL of sterile water and injected into a forearm vein within one
minute by the study physician. All medication was administered in the morning. Treatments were given in a
crossover design, with washout periods of >3 weeks between each dose. The study protocol was approved by
the ethics committee of the North-Rhine Medical Council, Düsseldorf, Germany, and the German
Bundesinstitut für Arzneimittel und Medizinprodukte.
Venous blood samples (5 mL) were collected using an indwelling cannula (Sarstedt Group, Sarstedt,
Germany) prior to ASA administration (baseline, 0) and 5, 30, 45, and 60 minutes and 1.5, 2, 3, 6, 8, and 24
hours after administration of oral ASA, and one, 3, 5, 10, 15, 20, 30, 40, and 60 minutes and 1.5, 2, 3, 6, 8,
and 24 hours after administration of intravenous ASA. Blood for pharmacokinetic analysis was collected into
lithium heparin monovettes containing approximately 50 mg of solid sodium fluoride. The plasma was
separated immediately and stored frozen at −70°C or below. Assays were performed within 3 months of
sampling. Blood samples for measurements of platelet aggregation were collected into citrated tubes and
centrifuged for 10 minutes at 100× g and room temperature to obtain plasma rich in platelets. After removal
of the plasma, the remaining blood was centrifuged for 10 minutes at 2,000× g to obtain plasma poor in
platelets. Platelet aggregation was measured as described below within 2 hours of sample collection. Blood
samples for measurement of serum thromboxane B2 and 6-keto-PGF1α were collected into Sarstedt tubes and
shaken for 30 minutes at 37°C to allow for coagulation. Serum was separated by centrifugation for 10
minutes at 2,000× g and stored in 0.5 mL fractions at −20°C or −70°C.
Urine samples were collected over 0–8 and 8–24 hours after drug administration and 9 mL samples were
stored frozen for analysis of ASA and salicylic acid.
Pharmacokinetics
Plasma concentrations of ASA and salicylic acid were measured by means of a validated and internally
standardized high-performance liquid chromatography assay. The method employed liquid/liquid extraction
using diethylether under acidic conditions, followed by reverse-phase chromatography on an Aqua C18®
column (Phenomenex, Niederlassung, Germany). The analytes and the internal standard (2-acetylbenzoic
acid) were measured by ultraviolet detection at 230 nm. The linear regression curves were calculated from
peak height ratios versus spiked concentrations, with 1/x2 weighing. For each analyte, two independently
prepared stock solutions in lithium heparin human plasma stabilized with sodium fluoride (3 mg/mL) were
used for preparation of calibration standards and quality control samples. The lower limits of quantification
for ASA and salicylic acid in plasma were 0.29 mg/L and 0.66 mg/L, respectively, and the precision ranged
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Pharmacokinetic parameters were calculated by model-independent (compartment-free) methods using
WinNonlin® software, version 4.1.a. (Pharsight Corporation, Mountain View, CA, USA). The primary
pharmacokinetic parameters were the area under the plasma concentration versus time curve from zero to
infinity after study drug dosing divided by the dose (AUC0–∞/D), Cmax divided by dose (Cmax/D), and absolute
bioavailability (F). Secondary plasma pharmacokinetic parameters were AUC0–∞, Cmax, time to reach
maximum drug concentration in plasma (Tmax), and the half-life associated with the terminal slope (t½).
Other parameters included clearance (CL) or apparent clearance (CL/f) for intravenous and oral application
respectively, and amount excreted in urine (Ae).
Platelet aggregation and thromboxane B2 production

Measurements of platelet aggregation were carried out by light transmission aggregometry. Platelet-poor
reference plasma was used to calibrate a 100% aggregation level, and the transmission of the platelet-rich
sample to be analyzed was converted to percentage values of aggregation accordingly. Platelet aggregation
was triggered by addition of 20 μL of 10 mM arachidonic acid to 180 μL of the platelet-rich plasma sample.
Serum thromboxane B2 and 6-keto-PGF1α concentrations were determined in serum by radioimmunoassay
following in vitro conversion of thromboxane A2 and PGI2, respectively. The radioimmunoassays used
polyclonal rabbit antisera previously generated and validated in the analytical laboratory. The lower limits of
quantification were 100 pg/mL and 250 pg/mL for thromboxane B2 and 6-keto-PGF1α, respectively.

Adverse events
Adverse events were identified by: questioning at baseline, 20 minutes, 3 hours, and 24 hours after
intravenous dosing; by questioning at baseline and at 1, 3, and 24 hours after oral dosing; and by
spontaneous reporting throughout the study. Adverse events were recorded by the investigator and classified
according to the Medical Dictionary for Regulatory Activities (MedDRA, version 9.1). The severity of adverse
events was rated as mild (usually transient and generally not interfering with normal activities), moderate
(sufficiently discomforting to interfere with normal activities), or severe (preventing normal activities).
Treatment-emergent adverse events were defined according to the International Conference on
Harmonization E9 guidelines as events that emerged during treatment, having been absent pretreatment, or
that worsened relative to the pretreatment state.14
Statistical analysis

The statistical analysis was performed using SAS® software (version 8.2, Cary, NC, USA). The concentration-
time courses of ASA and salicylic acid were calculated as geometric means with geometric coefficients of
variation, except for Tmax, for which medians were reported. Log-transformed primary pharmacokinetic
parameters were analyzed using analysis of variance including sequence, subject (sequence), period, and
treatment effects. Point estimates (least squares means) and exploratory 90% confidence intervals for drug
ratios were calculated by retransformation of the logarithmic data using the intraindividual standard deviation
of the analysis of variance.
Descriptive statistics were used for analyzing platelet aggregation, lag time of aggregation, and thromboxane
B2 and 6-keto-PGF1α concentrations. Because of the “all-or-none” nature of platelet aggregation, aggregation
values below 10% (the threshold for discrimination of noise from true aggregation) were replaced by zero in
the statistical analysis. Dose-effect relationships for intravenous and oral treatments were evaluated by
correlation analysis (Spearman’s correlation coefficient, rho). Comparisons of the pharmacodynamic
parameters between treatments were performed by nonparametric Wilcoxon tests.
All statistical analyses were performed without adjustment for multiple comparisons, and with unadjusted
significance levels of α =0.05. No formal sample size calculation was performed due to the exploratory nature
of the study. Equivalence was determined using the standard ranges (0.8–1.25 90% confidence interval
ranges).
Results
Subjects
The study was carried out in 14 healthy male and eight healthy female volunteers with a mean age of 49
(range 40–58) years) and a mean body mass index of 26 ± 3.9 kg/m2. All 22 subjects received at least one
dose of trial medication and were included in the safety analysis. A total of 21 subjects completed all six
study periods and were included in the pharmacodynamic and pharmacokinetic analyses.
Pharmacokinetics of ASA according to route of administration
The derived pharmacokinetic parameters for single doses of intravenous and oral ASA are summarized in
Table 1 and the estimates for salicylic acid are summarized in Table 2. There were differences in the
pharmacokinetic variables between the formulations, as expected due to the differing modes of
administration. The median Tmax was much shorter with intravenous ASA than with oral ASA (0.017 versus
0.500 hours, respectively), and both Cmax and AUC0–∞ were higher (Cmax, geometric mean 54.25 mg/L with
ASA 500 mg intravenously versus 4.84 mg/L with ASA 500 mg orally; and AUC0–∞, geometric mean 10.31
mg · hour/L with ASA 500 mg intravenously versus 5.12 mg · hour/L with ASA 500 mg orally). In most cases,
dose to
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the 90% confidence interval for the ratio of AUC0–∞/D was higher than the prespecified limit of 1.25. The
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variability of the AUC0–∞ of ASA was considerably higher after oral ASA than after intravenous ASA.
internal purposes and for sharing information with our business partners. You can learn about what data of yours we retain,
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Table 1 Geometric shared(geometric
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Abbreviations: ASA, acetylsalicylic acid; AUC0–∞, area under the plasma concentration versus time
curve from zero to infinity; AUC0–∞/D, geometric mean dose-corrected area under the curve; CL
clearance; CL/f, apparent clearance; Cmax, peak plasma concentration; Cmax/D, geometric mean dose-
corrected peak concentration; iv, intravenously; po, orally; F, absolute bioavailability; Tmax, time to
reach maximum drug concentration in plasma; t½, half-life associated with the terminal slope.

Table 2 Geometric means (geometric coefficients of variation, %) and ranges for pharmacokinetic
parameters of salicylic acid following administration of acetylsalicylic acid 250 mg and 500 mg
intravenously and acetylsalicylic acid 100 mg, 300 mg, and 500 mg orally
Note: aMedian.
Abbreviations: Ae, cumulative amount excreted into urine; ASA, acetylsalicylic acid; AUC0–∞, area
under the plasma concentration versus time curve from zero to infinity; AUC0–∞/D, geometric mean
dose-corrected area under the curve; CL clearance; CL/f apparent clearance; Cmax, peak plasma
concentration; Cmax/D, geometric mean dose-corrected peak concentration; iv, intravenously; po,
orally; Tmax, time to reach maximum drug concentration in plasma; t½, half-life associated with the
terminal slope.
Platelet aggregation and thromboxane B2 production

The effect of intravenous and oral ASA on arachidonic acid-induced platelet aggregation is shown in Figure 1.
Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous ASA doses,
whereas this was not found following any of the oral doses. The mean (standard deviation) platelet
aggregation values at 5 minutes were 87.4% ± 10.7%, 75.6% ± 36.2%, and 66.1% ± 39.7% with ASA
doses of 100, 300, and 500 mg orally, respectively. Complete inhibition was achieved by 20 minutes with ASA
300 mg and 500 mg orally, while the remaining mean platelet aggregation value was 31.6% ± 46.0% for
ASA 100 mg orally at this time point. Complete inhibition with ASA 100 mg orally was seen after 40 minutes.
The mean platelet aggregation with intravenous placebo was 92.0% ± 10.7% at 5 minutes and 89.0% ±
9.9% at 3 hours, reflecting normal platelet function in the study participants in the absence of any aspirin
treatment.

Figure 1 The mean (standard deviation) inhibition of arachidonic acid-induced platelet aggregation
measured after administration of a single dose of ASA administered intravenously (250 mg or 500
mg) or orally (100, 300, or 500 mg), or saline (placebo intravenously).
Abbreviations: ASA, acetylsalicylic acid; iv, intravenously; po, orally.
The mean serum thromboxane B2 concentrations at 5 minutes after intravenous drug administration were
0.82 ± 0.81 ng/mL for ASA 250 mg intravenously and 0.69 ± 2.21 ng/mL for ASA 500 mg intravenously,
which translated into a mean reduction of 99.3% ± 1.5% and 99.7% ± 0.9%, respectively (Figure 2). There
was a significant difference between intravenous doses at this time point (P<0.0001, Wilcoxon test), and a
negative correlation between intravenous doses and thromboxane B2 concentrations (Spearman’s rho
=−0.57). The mean serum thromboxane B2 concentrations at 5 minutes after oral drug administration were
157.01 ± 92.44 ng/mL with ASA 100 mg orally, 108.33 ± 58.43 ng/mL with ASA 300 mg orally, and 83.74 ±
55.49 ng/mL with ASA 500 mg orally. There was a significant difference at 5 minutes after administration
between ASA 100 mg orally and ASA 300 mg orally (P=0.0091, Wilcoxon test), and between ASA 100 mg
orally and ASA 500 mg orally (P=0.0009, Wilcoxon test). At this time point, there was a negative correlation
between oral doses and thromboxane B2 concentrations (Spearman’s rho =−0.37). ASA doses of 300 mg
orally and 500 mg orally did not produce clinically relevant inhibition of platelet function (>95% reduction in
thromboxane B2) within 20 minutes, and the 100 mg oral dose did not reach this threshold at any time point;
the maximum inhibition of thromboxane B2 with ASA 100 mg orally was 89.4%. There were significant
differences in thromboxane B2 concentrations between ASA 500 mg intravenously and ASA 500 mg orally at
5, 20, 40, and 60 minutes (all P<0.0001, Wilcoxon test).

Figure 2 Mean serum TXB2 concentrations after administration of a single dose of ASA
administered either intravenously (250 mg or 500 mg) or orally (100, 300, or 500 mg), or saline
(placebo intravenously). Data are presented using a semilogarithmic scale.
Abbreviations: ASA, acetylsalicylic acid; iv, intravenously; po, orally; TXB2, thromboxane B2.

The time course of the reductions in serum 6-keto-PGF1α concentrations following administration of ASA is
shown in Figure 3. Concentrations declined rapidly within 5 minutes with both intravenous ASA doses
compared with oral ASA doses. There was evidence of dose-related reductions in serum 6-keto-PGF1α with
oral ASA. The serum 6-keto-PGF1α concentrations following administration of ASA 500 mg intravenously and
ASA 500 mg orally differed significantly at 5 minutes (mean difference −0.061 ng/mL, P=0.0002) and 20
minutes (mean difference −0.015 ng/mL, P=0.0086), but not at 40 minutes (mean difference −0.004 ng/mL,
P=0.7216).
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Figure 3 MeanPolicy.
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(placebo).
Abbreviations: ASA, acetylsalicylic acid; iv, intravenously; po, orally; 6-keto-PGF, 6-keto-
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Adverse events
There were no serious adverse events in any subject following administration of either intravenous or oral
ASA at any of the doses studied. In total, 15 subjects reported at least one treatment-emergent adverse
event, all but two of which were mild in intensity; headache and migraine, both of moderate intensity, were
each reported by one subject after administration of intravenous placebo. There were no differences between
the five active treatments in the incidence and spectrum of treatment-emergent adverse events.
Discussion
Differences in onset of action have implications for determining the minimally effective dose that should be
used in an intravenous preparation and also for the adverse event profile. The current study showed that
although intravenous ASA had a faster onset of action than oral ASA, with a Tmax of 0.02 hours and 0.5
hours, respectively, the geometric mean Cmax/D was 11 times higher with intravenous than oral ASA 500 mg
(estimated ratio 11.23) and the geometric mean AUC0–∞/D was twice as high (estimated ratio 2.03). For
salicylic acid, there was a slight increase in AUC0–∞/D with dose (estimated ratio 1.41 for ASA 500 mg
intravenously versus ASA 250 mg intravenously), which was expected. The current study also shows that
there were no clinically relevant differences in treatment-emergent adverse events, but using a lower
intravenous dose might have implications in this regard, particularly in relation to renal adverse events.
However, this was beyond the scope of our study.
Clinically relevant inhibition of platelet function, defined as >95% reduction in serum thromboxane B2
concentrations from baseline, was achieved with intravenous ASA within 5 minutes of dosing. The mean
inhibition of serum thromboxane B2 was 99.3% and 99.7% with intravenous ASA 250 mg and 500 mg,
respectively. Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous
ASA doses. By contrast, complete inhibition was only achieved by 20 minutes with ASA 300 mg and 500 mg
administered orally, and incomplete inhibition of platelet aggregation with ASA 100 mg orally was observed at
this time (the mean residual aggregation value was only 31.6% ± 46.0%). The difference in serum
thromboxane B2 reductions between ASA 500 mg intravenously and ASA 500 mg orally was statistically
significant at each time point up to one hour after administration (P<0.0001).
The study also determined the effect of ASA on serum 6-keto-PGF1α, which is a surrogate measure of PGI2
formation. It likely reflects both vascular PGI2 synthesis in vivo as well as PGI2 synthesis by leukocytes
during in vitro coagulation of the serum samples. While intravenous ASA and the higher doses of oral ASA
reduced thromboxane B2 production by at least two orders of magnitude, the maximum inhibition of 6-keto-
PGF1α production following oral or intravenous ASA was only ten-fold or less. This lower inhibition may reflect
the fact that ASA has some selectivity for the COX-1 isoform,15 and that COX-1 largely predominates in
platelets compared with COX-2, which is expressed in vascular and inflammatory cells. It has been shown
that long-term suppression of PGI2 formation may augment injury-induced atherogenesis and platelet
activation,16 although the clinical relevance of PGI2 inhibition by ASA in cardiovascular disease is unclear. The
present results demonstrate that, at doses of 250–500 mg, administration of ASA either orally or
intravenously has comparable effects on PGI2 synthesis, because there were few significant differences in 6-
keto-PGF2α concentrations following intravenous or oral dosing, except at 5 and 20 minutes after dosing with
500 mg. A hypothetical adverse effect of intravenous ASA on vascular integrity resulting from higher
exposure of PGI2-forming vascular cells to ASA is therefore unlikely. It is of note that in this study ASA orally
was administered in the fasted state and that the tablets were chewed and swallowed with 240 mL of tap
water at room temperature thereafter. These conditions may have facilitated absorption and led to an
“optimized” effect on COX inhibition.
Studies in animals have also shown that biochemical selectivity is not apparent with intravenous ASA. An
intravenous or oral dose of ASA 5 mg/kg administered to rats resulted in comparable inhibition of portal vein
6-keto-PGF1α and thromboxane B2, but formation of inferior vena cava 6-keto-PGF1α was spared.5 In humans,
administration of intravenous or oral ASA 1 g was found to completely suppress serum thromboxane B2, but
urinary thromboxane B2 and 6-keto-PGF1α were also suppressed by intravenous ASA.10,17 Oral ASA is a renal-
sparing drug compared with other nonsteroidal anti-inflammatory agents; however, in the present study, only
one renal/urinary disorder adverse event was reported with ASA 500 mg intravenously.
The present study characterizing the pharmacokinetics and pharmacodynamics of ASA in healthy subjects
has some limitations. The need to perform platelet function assays immediately after blood sampling and the
yes/no character of the response preclude the possibility of more accurately characterizing the time-
dependency and dose-dependency of effects on platelet aggregation after intravenous and oral ASA
administration. In addition, disease-related factors may affect the measurement of arachidonic acid-induced
platelet activation in patients with acute coronary syndrome. By contrast, serum thromboxane B2
measurements showed more time-related, treatment-related, and dose-related effects of intravenous and
oral ASA treatment. As described above, synthesis of thromboxane B2 was almost completely (>95%)
inhibited within 5 minutes of treatment with intravenous ASA, and remained low with both intravenous doses.
By contrast, with 300 mg and 500 mg of oral ASA, a comparable decrease in thromboxane B2 was not seen
until about 40 minutes after administration, and the maximum inhibition of thromboxane synthesis after oral
intake
In order toof 100 mg
provide ourASA was 89.4%.
website visitorsThe
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interindividual variability in the inhibition of thromboxane synthesis than with intravenous administration. Accept
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Despite these limitations, the study shows that intravenous ASA provides rapid and consistent inhibition about our use of of
platelet
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by reading in healthy volunteers.
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We also on its
retain datapharmacokinetic/pharmacodynamic profile,users
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250 mg
given intravenously may be useful where rapid inhibition of platelet function is required, such as in the acute
internal purposes and for sharing information with our business partners. You can learn about
management of patients with acute coronary syndrome, and the findings of this study justify comparison what data of yours
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processed, and oral
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guidelines.18 Intravenous ASA could also be beneficial in acute-phase Kawasaki disease, where poor
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In summary, this study is novel in that it is one of the first to compare intravenous and oral ASA at doses
routinely used in the clinical setting and thus generates clear and comparable pharmacokinetic and
pharmacodynamic surrogate marker data. For intravenous ASA treatment specifically, it shows the immediate
onset of action supported by pharmacokinetic data that describe the action in an acute cardiovascular clinical
setting. Extensive research has been performed on the activity of oral ASA, establishing markers of platelet
inhibition and aggregation that are widespread as assays today.20–22 The findings of such studies have also
established the optimal doses of oral ASA for clinical use, and research groups are currently exploring the
intricacies of its mode of action and most effective dosing strategies in more detail.23–25 A study in 41
patients with unstable angina was one of the first to explore the effects of intravenous ASA (60 mg on the
first treatment day and 20 mg on successive days).26 The study showed that serum thromboxane B2
decreased from 160 ng/mL to <6 ng/mL (around 96% reduction). Although the reduction was sufficient for
effective clinical inhibition, it was still not 100% complete. Overall, this study showed that ASA was not
superior to coronary vasodilators (isosorbide dinitrate and oral diltiazem) and patients remained at risk of
myocardial ischaemia. Consequently, these authors recommended early aggressive treatment in an acute
setting. In the present study, the thromboxane B2 concentration was negligible at 5 minutes with ASA 250
mg intravenously (0.82 ng/mL). Our findings indicate that this dose of ASA could be more beneficial in an
acute setting, and these results will be of interest to those devising guidelines for the most appropriate
combination strategies in this environment.
Acknowledgments
The bioanalytical work for ASA and SA was conducted at the laboratory of Dr Ulf Buetehorn. The authors also
gratefully acknowledge the technical assistance of Irmhild Rüter.
Disclosure
JN, MB, JK, ML, and GW are employees of Bayer HealthCare AG. TH declares no conflict of interest in this
work. The study and analyses were funded by Bayer HealthCare AG.

References
1. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal
antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S
A. 1993;90(24):11693–11697.
2. Cham BE, Ross-Lee L, Bochner F, Imhoff DM. Measurement and pharmacokinetics of acetylsalicylic acid by
a novel high performance liquid chromatographic assay. Ther Drug Monit. 1980;2(4):365–372.
3. Smith WL. Molecular mechanisms of aspirin action. Drug News Perspect. 1991;4:362–366.
4. Prosdocimi M, Finesso M, Gorio A, et al. Coronary and systemic 6-ketoprostaglandin F1 alpha and
thromboxane B2 during myocardial ischemia in dog. Am J Physiol. 1985;248(4 Pt 2):H493–H499.
5. Cerletti C, Gambino MC, Garattini S, de Gaetano G. Biochemical selectivity of oral versus intravenous
aspirin in rats. Inhibition by oral aspirin of cyclooxygenase activity in platelets and presystemic but not
systemic vessels. J Clin Invest. 1986;78(1):323–326.
6. FitzGerald GA, Lupinetti M, Charman SA, Charman WN. Presystemic acetylation of platelets by aspirin:
reduction in rate of drug delivery to improve biochemical selectivity for thromboxane A2. J Pharmacol Exp
Ther. 1991;259(3):1043–1049.
7. Muir N, Nichols JD, Clifford JM, Stillings MR, Hoare RC. The influence of dosage form on aspirin kinetics:
implications for acute cardiovascular use. Curr Med Res Opin. 1997;13(10):547–553.
8. Rowland M, Rielgelma S. Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous
administration in man. J Pharm Sci. 1968;57(8):1313–1319.
9. Broome TA, Brown MP, Gronwall RR, Casey MF, Meritt KA. Pharmacokinetics and plasma concentrations of
acetylsalicylic acid after intravenous, rectal, and intragastric administration to horses. Can J Vet Res.
2003;67(4):297–302.
10.FitzGerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in
cardiovascular disease. Circulation. 1983;67(6):1174–1177.
11.Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients
with unstable angina/non ST-elevation myocardial infarction: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the
2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial
Infarction): developed in collaboration with the American Association of Cardiovascular and Pulmonary
Rehabilitation and the Society for Academic Emergency Medicine. Circulation. 2007;116:e148–e304.
12.Gerrard JM. Measurements of 6-keto-prostaglandin F1 alpha and thromboxane B2 in bleeding time blood:
relation to bleeding and vascular disorders? Can J Physiol Pharmacol. 1989;67(8):922–928.
13.Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance
after coronary artery bypass surgery. Circulation. 2003;108(5):542–547.
14.European
In order to provideMedicines Agency.
our website ICHand
visitors Topic E9. Statistical
registered users principles for clinical
with a service tailoredtrials. Available
to their from:
individual
http://www.ema.europa.eu/pdfs/human/ich/036396en.pdf. Accessed June 6, 2011. Accept
preferences we use cookies to analyse visitor traffic and personalise content. You can learn about our use of
15.Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38:97–
cookies by reading our Privacy Policy. We also retain data in relation to our visitors and registered users for
120.
internal purposes and for sharing information with our business partners. You can learn about what data of yours we retain,
how16.Cheng Y, Austin
it is processed, who SC, Rocca
it is B, et
shared al.and
with Roleyour
of prostacyclin
right to havein your
the cardiovascular
data deleted by response
readingto thromboxane
our A2.
Privacy Policy.
Science. 2002;296(5567):539–541.
If you agree to our use of cookies and the contents of our Privacy Policy please click 'accept'.
17.Cerletti C, Gambino MC, Bucchi F, Rajtar G, Riva E, de Goetano G. Comparison of the effects of oral and
intravenous aspirin administration on platelet and peripheral vascular cyclo-oxygenase activity: studies in
https://www.dovepress.com/pharmacokinetics-and-pharmacodynamics-of-acetylsalicylic-acid-after-in-peer-reviewed-fulltext-article-CPAA 6/7
24/10/2020 [Full text] Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after in | CPAA
rats and in man. Agents Actions Suppl. 1986;20:239–248.
18.Hamm CW, Bassand J-P, Agewall S, et al. ESC guidelines for the management of acute coronary
syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J.
2011;32(23):2999–3054.
19.Ito S, Oka R, Tsuchida A, Yoshioka H. Disposition of single-dose intravenous and oral aspirin in children.
Dev Pharmacol Ther. 1991; 17(3–4):180–186.
20.Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of
atherothrombosis. N Engl J Med. 2005;353(22):2373–2383.
21.Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by
low-dose aspirin in healthy subjects. J Clin Invest. 1982;69(6):1366–1372.
22.FitzGerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and
platelet function during chronic administration of aspirin in man. J Clin Invest. 1983;71(3):676–688.
23.Dillinger JG, Drissa A, Sideris G, et al. Biological efficacy of twice daily aspirin in type 2 diabetic patients
with coronary artery disease. Am Heart J. 2012;164(4):600–606.
24.Rocca B, Santilli F, Pitocco D, et al. The recovery of platelet cyclooxygenase activity explains
interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J
Thromb Haemost. 2012;10(7):1220–1230.
25.Pascale S, Petrucci G, Dragani A, et al. Aspirin-insensitive thromboxane biosynthesis in essential
thrombocythemia is explained by accelerated renewel of the drug target. Blood. 2012;119(15):3595–
3603.
26.Vejar M, Hackett D, Brunelli C, et al. Comparison of low-dose aspirin and coronary vasodilators in acute
unstable angina. Circulation. 1990;81 Suppl I:I4–I11.

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