ORIGINAL ARTICLE

Asian Pacific Journal ofAllergy and Immunology

Systemic absorption of epinephrine compared between
the intranasal and intramuscular routes of administrationin healthy adults
Chatchawan Srisawat,1,2 Rattana Pipitpreecha,3 Weerawadee Chandranipapongse,4 Somruedee Chatsiricharoenkul,4
Piyapat Pongnarin,4 Supornchai Kongpatanakul,4 Apirom Laocharoenkiat,5 Orathai Jirapongsananuruk,3Nualanong Visitsuntorn,3 Pakit Vichyanond3

Abstract
Background: Epinephrine 5 mg administered via the intranasal (IN) route was shown to be bioequivalent to epinephrine 0.3 mg administered via the intramuscular (IM) route in our preliminary study.
Objective: To investigate the pharmacokinetics and pharmacodynamics of IN and IM epinephrine absorption in alarger group of healthy adults (n = 12).
Methods: Each subject was administered IN saline, IN epinephrine (5 mg), and IM epinephrine (0.3 mg) on 3 separate
days. Plasma epinephrine levels were determined using liquid chromatography-tandem mass spectrometry.
Results: IN epinephrine administration showed significant systemic absorption compared to IN saline control withthe areas under the curve (AUC0-180 min) of 4.4 (4.9) ± 4.0 and 0.2 (0.5) ± 0.3 ng.min/mL, respectively; the values aremean (median) ± standard deviation. IN epinephrine absorption was about 0.5-fold that of IM epinephrine (AUC0-180 min
10.0 (9.2) ± 8.6 ng.min/mL), but the difference was not statistically significant (p = 0.16). The mean peak epinephrine concentration and the time to reach it were also not significantly different between the IN and IM routes.
The corresponding values were 120 pg/mL and 41 min for IN, and 209 pg/mL and 41 min for IM, respectively.
Conclusion: The systemic absorption of IN epinephrine 5 mg was significantly different from the control IN saline andabout 0.5-fold that of IM epinephrine 0.3 mg. Although epinephrine administration via the less invasive IN route is safeand feasible, further investigations are necessary to achieve an adequate and consistent systemic absorption comparable
to that of the conventional IM injection.
Key words: epinephrine, intranasal administration, intramuscular injection, pharmacokinetics, pharmacodynamics,
anaphylaxis

Affiliations:1
Department of Biochemistry, Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok, Thailand
2
Siriraj Metabolomics and Phenomics Center, Faculty of Medicine
Siriraj Hospital, Mahidol University, Bangkok, Thailand
3
Department of Pediatrics, Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok, Thailand
4
Department of Pharmacology, Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok, Thailand
5
Pharmacy Department, Siriraj Hospital, Bangkok, Thailand
Corresponding author:
Pakit Vichyanond
Division of Allergy and Immunology, Department of Pediatrics,
Faculty of Medicine Siriraj Hospital, Mahidol university,
Bangkok 10700, Thailand
E-mail: pakit.vic@mahidol.ac.th

Introduction

Epinephrine is the drug of choice for initial treatmentof anaphylaxis. It is, therefore, strongly recommended thatpatients with a history of severe anaphylactic reaction (ortheir caregivers) have an epinephrine auto-injector readily
available for intramuscular (IM) injection as first aid treatment.1,2 However, IM epinephrine administration is often
underused for various reasons, including unavailability of
auto-injectors (particularly in developing countries) due totheir relatively high cost;3,4 lack of confidence in using thedevice, which requires proper instruction, repeated training,and practice;5 and fear of needles.6

Asian Pac J Allergy Immunol DOI 10.12932/AP-120821-1209

Alternative routes of epinephrine administration
have been investigated to overcome the drawbacks of IM
injection.7 The intranasal (IN) route is a potential route of
drug administration in this setting because the nasal mucosa
consists of highly vascularized and permeable tissue withhigh absorption capability. Previous studies in canine model
demonstrated that epinephrine administered via the IN route
readily absorbed into the systemic circulation.8,9 In humans,
systemic epinephrine absorption was reported after topicalapplication for endoscopic sinonasal surgery.10-12 A preliminary study in a small group of healthy adults (n = 5) thatwas previously conducted by our group demonstrated that
IN epinephrine 5 mg could be systemically absorbed, andthe plasma concentration was bioequivalent to that of IM
epinephrine 0.3 mg.13 The aim of this study was to determine
and compare the pharmacokinetics and pharmacodynamics of IN epinephrine 5 mg with those of IM epinephrine 0.3
mg in a larger group of healthy subjects (n = 12) to confirm
our previous findings, and to evaluate for any side effects ofIN epinephrine administration.

Methods

Materials and Reagents
Epinephrine bitartrate was purchased from Sigma-Aldrich(St. Louis, MO, USA). An internal standard (lamivudine) was
obtained from the United States Pharmacopeial Convention,
Inc. (Rockville, MD, USA). Cationic exchange cartridges(1 cc Oasis MCX Vac cartridges, cat. no. 186000252) werepurchased from Waters Corporation (Milford, MA, USA).
Intranasal Epinephrine Spray Formulation and Administration
Intranasal (IN) epinephrine spray was freshly prepared
before use by the Pharmacy Department of Siriraj Hospital(Bangkok, Thailand). A specified amount of epinephrine
bitartrate was dissolved in normal saline solution to a
final concentration of 40 mg/mL and filter-sterilized. The
nasal spray device dispensed 5 mg of epinephrine in 125 ± 4
μL volume per puff (coefficient of variation of device output= 4%). Before IN administration, subjects underwent nasal
irrigation with normal saline solution. To deliver the nasal
spray, the tip of the device was inserted into the nasal cavity
adjacent to the inferior turbinate and the spray was administered into one nostril.
Subject Selection
The study was conducted according to the guidelinesof the Declaration of Helsinki, and approved by the Siriraj
Institutional Review Board (SiRB) of Faculty of Medicine
Siriraj Hospital, Mahidol University (approval no. SI258/2007).
The study protocol was also registered in the ClinicalTrials.
gov website (reg. no. NCT01432522). Twelve healthy subjects(4 males, 8 females) aged 18-30 years were recruited andinformed consent was obtained from all subjects involved in
the study. Subjects were determined to be healthy based on
evaluation of normal medical history, physical examination,and laboratory investigations, including electrocardiographic(ECG) study and routine hematological, biochemical, andurinary analyses. Subjects were excluded if they had

underlying diseases (e.g., cardiovascular disease, hypertension,or systemic diseases), history of smoking, use of any drug, or
recent upper respiratory tract infection.
Study Design and Outline
On 3 separate days (at least 14 days apart), each subject
was given the following treatments: 1) IN spray of normal
saline solution as a negative control; 2) IM injection of
epinephrine USP 1:1,000 at 0.3 mg (0.3 mL) in the lateralpart of the right thigh as a positive control; and, 3) IN spray
containing 5 mg of epinephrine bitartrate. Foods containing
methylxanthine, such as chocolate, cocoa, and cola, were disallowed for at least 24 hours before each study day. On eachstudy day, an indwelling venous catheter was inserted forblood sample collection, and blood pressure, heart rate, andECG were continuously monitored. Venous blood samples
were collected from the indwelling venous catheter for plasma
concentration measurement at various time points, including
at 30 and 15 minutes before the treatment (as baseline or time0), and at 5, 10, 15, 20, 30, 45, 60, 90, 120, and 180 minutes
after the treatment. For each collection, 10 mL of whole blood
was mixed in a heparin tube containing 75 μL of EGTAglutathione solution (9.5% EGTA and 3% glutathione, pH
6-7). All samples were put on ice and processed within 1 h
after collection by spinning down at 1,600 g for 10 min at
4°C to collect plasma, which was then stored in light-resistantpolypropylene tubes at -80°C until analysis.
Determination of Plasma Epinephrine Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method
Frozen plasma was thawed at room temperature before
sample preparation by solid phase extraction (SPE). Briefly,
500 μL of plasma, 20 μL of 0.5 μg/mL lamivudine (internal
standard), and 550 μL of deionized water were gently mixed
and transferred into an SPE cartridge (Oasis MCX 1 cc;
Waters Corporation) that was pre-conditioned with methanoland deionized water. The sample-loaded SPE cartridge wasthen washed with 3 mL of 2% formic acid. The analytes were
eluted with 1 mL of 5% NH4OH in methanol. The eluate was
evaporated under nitrogen stream at 30°C and reconstituted
in 100 µL of 0.1% formic acid before quantification using
LC-MS/MS method.
For LC-MS/MS analysis of epinephrine, the liquid chromatographic separation was performed using an Acquity™
Ultra Performance LC (Waters Corporation) and a C18
column (Gemini® NX C18, 3 μm, 150 × 2.0 mm Phenomenex, Torrance, CA, USA). The mobile phase consisted of
2% formic acid in water (A) and 100% acetonitrile (B).
The separation was run at a flow rate of 0.2 mL/min using
the following gradient elution profile: 0-2 min, 2% B; 2-3
min, 2%-10% B; 3-3.5 min, 10% B; 3.5-4.5 min, 10%-2%
B; and 4.5-6 min, 2% B (for a total run time of 6 minutes).
The retention times for epinephrine and lamivudine were
2.2 minutes and 4.3 minutes, respectively. For mass spectrometry (MS) analysis, the mass spectra were analyzed
using a Quattro Premier™ XE Tandem Quadrupole Mass
Spectrometer (Waters Corporation). Multiple reaction monitoring (MRM) mode was used with electrospray ionization(ESI) source in positive mode. The mass transition ion-pairs

Intranasal epinephrine pharmacokinetics

for epinephrine [M + H]+ ions were selected as 184.07 >106.98 and 184.07 > 166.07 m/z. For lamivudine, the masstransition ion-pair was 230.11 > 111.97 m/z. Data acquisition
was performed using MassLynx 4.1 mass spectrometry software (Waters Corporation).
Data Analysis
To determine the rate and extent of epinephrine absorption, the area under the plasma concentration-time curve attime 0-180 minutes (AUC0-180 min) was calculated using thelinear trapezoid method. In this calculation, the difference
between the plasma epinephrine concentration at each time
point and the baseline plasma epinephrine concentration
was used to determine the baseline-adjusted AUC0-180 min.
Statistical analysis was performed using GraphPad Prism 9.1.0(GraphPad Software Inc., San Diego, CA, USA). The pharmacokinetic parameters Cbaseline, Tmax and AUC0-180 min wereanalyzed using Dunnett’s T3 post hoc test following BrownForsythe analysis of variance (ANOVA). For Cmax, the valuesof which were not normally distributed, Kruskal-Wallis
test followed by Dunn’s multiple comparison test was used.
Differences were considered statistically significant at a
p-value less than 0.05.

Results

In this study, 12 healthy adults were recruited, and eachsubject received IN saline, IN epinephrine 5 mg, and IM epinephrine 0.3 mg on separate days (at least 14 days apart). As
shown in Figure 1A and 1B, IN epinephrine 5 mg showedsignificantly higher systemic absorption over 180 minutes
compared to that of IN saline. The corresponding AUC0-180 min

Plasma epinephrine (pg/mL)A(mean [median] ± standard deviation) was 4.0 (4.9) ±4.0 and 0.2 (0.5) ± 0.3 ng.min/mL respectively; p = 0.02).
Epinephrine absorption was not significantly different
between the IN route and the IM route (p = 0.16); however,the AUC0-180 min for IN epinephrine was about 0.5-fold thatfor IM epinephrine (10.0 [9.2] ± 8.6 ng.min/mL). The otherpharmacokinetic parameters, i.e., plasma epinephrine
concentration at baseline (Cbaseline), peak plasma epinephrine
concentration (Cmax), and time to reach Cmax (Tmax), were also
not significantly different between the IM and IN routes of
epinephrine administration (Figure 1C-E). The Cmax values
for the IM and IN groups were 209 ± 228 and 120 ± 53 pg/
mL, and the Tmax values were 41 ± 41 and 41 ± 34 minutes,
respectively. All pharmacokinetic parameters for the threeadministrations are summarized in Table 1.
During the study, increases in heart rate and blood pressure (both diastolic and systolic) were consistently observedat the time of peak plasma epinephrine concentration during
both IN and IM epinephrine administrations. Transient andmild adverse reactions were observed after IN epinephrine
treatment in this study. One subject experienced short-term
palpitation during the study period, ten subjects felt transient nasal stinging, and another had bloody mucus nasal
discharge. All adverse reactions were resolved within one day.
For IM epinephrine injection, a serious adverse event wasobserved in one female subject. She developed hypotension,bradycardia and chest pain within 5 minutes after the injection, which was treated with intravenous saline loading. Afterconsultation with cardiologists, a right coronary artery spasm
was suspected; however, her symptoms resolved spontaneously and no further treatment was required.

250
200
150
100
50
0

0

30

60

90
120
Time after administration (min)IN Saline

IN Epi 5 mg

150

180

IM Epi 0.3 mg

Figure 1. The pharmacokinetics of epinephrine (EPI) after administration of intranasal (IN) saline, IN epinephrine (5 mg),and intramuscular (IM) epinephrine (0.3 mg). A) Plasma epinephrine concentrations at different time points after saline or
epinephrine administration (mean ± standard error of the mean). B) Area under the plasma concentration-time curve from t= 0 to 180 minutes (AUC0-180 min). C) Baseline plasma epinephrine concentration (Cbaseline). D) Maximum plasma epinephrine
concentration (Cmax). E) Time at which maximum plasma epinephrine concentration is achieved (Tmax). The plots are shownas individual values and mean ± standard deviation. Significant difference is indicated as follows: *p < 0.05, **p < 0.01,
and ***p < 0.001. (Abbreviation: ns, non-significant).

Asian Pac J Allergy Immunol DOI 10.12932/AP-120821-1209

B

**

35

*

C

ns

100
ns

30

20

Cbaseline (pg/mL)

AUC0-180 min (ng.min/mL)

ns

80

25

15
10
5
0

ns

60

40

20

-5
-10

D

IN Saline

IN Epi 5 mg
***

1000

**

0

IM Epi 0.3 mg

Ens

IN Saline

IN Epi 5 mg

IM Epi 0.3 mg

ns

140

ns

ns

120

800

100
80
Tmax (min)Cmax (pg/mL)

600
400

60
40

200

20
0
-200

0

IN Saline

IN Epi 5 mg

IM Epi 0.3 mg-20

IN Saline

IN Epi 5 mg

IM Epi 0.3 mg

Figure 1. (Continued)
Table 1. Pharmacokinetic parameters of epinephrine after administration of intranasal saline, intranasal epinephrine(5 mg), and intramuscular epinephrine (0.3 mg)
Intranasal
SalineIntranasal
Epinephrine 5 mg

Intramuscular
Epinephrine 0.3 mg

Cbaseline (pg/mL)

34 (38) ± 19

32 (35) ± 14

40 (38) ± 18

Cmax (pg/mL)

61 (57) ± 23

120 (88) ± 53

209 (136) ± 228

Tmax (min)24 (20) ± 24

41 (30) ± 34

41 (33) ± 41

AUC0-180 min (ng.min/mL)

0.2 (0.5) ± 0.3

4.4 (4.9) ± 4.0

10.0 (9.2) ± 8.6

Parameters

Data presented as mean (median) ± standard deviation

Discussion

Nasal mucosa is a promising site for systemic drug absorption because it is rich in vasculature and is highly permeable.
Our previous study in 5 healthy adults13 showed that epinephrine 5 mg can be well absorbed into the systemic circulation
via nasal mucosa, and that its bioavailability is comparable tothat of IM epinephrine 0.3 mg. In the present study, which
was conducted in a larger group of 12 healthy subjects, we
confirmed the previous findings. Several studies in dogs

also showed comparable systemic absorption between IN
epinephrine 5 mg and IM epinephrine 0.3 mg.14,15 However,
we found that although the pharmacokinetic parameters(i.e., AUC0-180 min, Cmax and Tmax) of the IN 5 mg and IM 0.3
mg groups were not significantly different (p values of 0.16,> 0.99 and > 0.99, respectively), the amount of epinephrine
absorption via IN, based on the average AUC0-180 min and Cmax,
was about 0.5-fold that via IM. It is possible that the systemicIntranasal epinephrine pharmacokinetics

absorption of epinephrine via IN at 5 mg might not becomparable to that via IM at 0.3 mg but the differences could
not be statistically detected due to the seemingly inadequate
number of subjects. Therefore, further studies in larger sample
sizes are needed to confirm this notion.
In contrast to the IM epinephrine absorption, high variability in IN absorption among the subjects was observed.
As shown in Figure 2, some subjects had epinephrine
absorption via IN comparable to or even better than that
via IM. However, about one-thirds of the subjects (i.e., no.
2, 4, 6, and 10) showed poor nasal epinephrine absorption
with the level comparable to that of the control IN saline.
The inadequate systemic absorption would be of great
concern as it might result in treatment failure particularly

during life-threatening anaphylaxis. The inter-subject variation could be due to histological, anatomical, and physiological differences in the nasal cavity among our healthy subjects,
and these factors have been reported to impair IN epinephrine
absorption.16 One of the physiological factors, i.e., the nasal
cycle, which causes alternating partial congestion and decongestion of the nasal cavities in humans and other animals,17
has been shown to affect mucociliary clearance and IN
absorption.18,19 In this study, epinephrine was applied into one
randomly-selected nostril, which might be more or less optimal for drug delivery, resulting in low epinephrine absorption
in some subjects. Furthermore, variability of IN absorption
could be more pronounced if it is applied in the general population because the prevalence of common nasal disorders,
SUBJECT 2
Plasma epinephrine (pg/mL)

Plasma epinephrine (pg/mL)

SUBJECT 1
200
180
160
140
120
100
80
60
40
20
0

0

20

40

60

80
100
Time (min)

120

140

160

180

900
800
700
600
500
400
300
200
100
0

0

20

40

60

160
140
120
100
80
60
40
20
0

0

20

40

60

80
100
Time (min)

120

140

160

180

Plasma epinephrine (pg/mL)

Plasma epinephrine (pg/mL)

150
100
50

20

40

60

80
100
Time (min)

160

180

120

140

160

180

120

140

160

180

160
140
120
100
80
60
40
20
0

0

20

40

60

80
100
Time (min)SUBJECT 6

200

0

140

180

SUBJECT 5
250

0

120

SUBJECT 4

180

Plasma epinephrine (pg/mL)

Plasma epinephrine (pg/mL)

SUBJECT 380100Time (min)

120

140

IN Saline

160180
IN Epi 5 mg

600
500
400
300
200
100
0

0

20

40

60

80
100
Time (min)IM Epi 0.3 mg

Figure 2. Plasma epinephrine concentrations at different time points of each subject (no.1–12) after administration of intranasal(IN) saline, IN epinephrine 5 mg, and intramuscular (IM) epinephrine 0.3 mg.

Asian Pac J Allergy Immunol DOI 10.12932/AP-120821-1209

SUBJECT 8
Plasma epinephrine (pg/mL)

Plasma epinephrine (pg/mL)

SUBJECT 7
140
120
100
80
60
40
20
0

0

20

40

60

80
100
Time (min)

120

140

160

180

90
80
70
60
50
40
30
20
10
0

0

20

40

60

120
100
80
60
40
20
0

0

20

40

60

80
100
Time (min)

120

140

160

180

Plasma epinephrine (pg/mL)

Plasma epinephrine (pg/mL)

150
100
50

20

40

60

80
100
Time (min)

160

180

120

140

160

180

120

140

160

180

140
120
100
80
60
40
20
0

0

20

40

60

80
100
Time (min)SUBJECT 12

200

0

140

160

SUBJECT 11
250

0

120

SUBJECT 10

140

Plasma epinephrine (pg/mL)

Plasma epinephrine (pg/mL)

SUBJECT 980100
Time (min)

120

140

IN Saline

160180
IN Epi 5 mg

160
140
120
100
80
60
40
20
0

0

20

40

60

80
100
Time (min)IM Epi 0.3 mg

Figure 2. (Continued)
e.g., nasal polyps, allergic and non-allergic rhinitis, is quite
high (up to 40% of the population).20 These disorders affecting
nasal mucosa could potentially interfere with the IN absorption of epinephrine. Thus, the roles of these factors, both
physiological and pathological, in IN epinephrine absorption require further investigations to ascertain that systemic
absorption via IN is adequate and consistent in all subjects.
Several approaches could be used to improve the IN
epinephrine absorption to achieve the bioavailability comparable to that of the conventional IM injection. For example,
IN epinephrine at higher doses (> 5 mg) and concentrations(> 40 mg/mL) should be studied; more epinephrine could
theoretically be absorbed across the nasal mucosa due tothe increased amount and concentration gradient. In addition, the nasal spray should be prepared using formulations

that offer superior physicochemical stability of epinephrine,
both ex-vivo and in-vivo (e.g., using a buffer solution with
an optimal pH and/or addition of antioxidants). Drugs withvasodilatation effect (e.g., alpha-adrenergic receptor antagonist, such as phentolamine) might be added into the formulation to reduce the vasoconstriction effect of epinephrine,
which prevents its own systemic absorption.9 Moreover, theuse of absorption enhancers may increase intranasal epinephrine absorption. Several different absorption enhancers havebeen used to improve intranasal delivery of various drugs inpreclinical studies.21-24 Recent studies investigated intranasal
epinephrine absorption of an epinephrine nasal spray (ARS-1)
that includes an absorption enhancer (Intravail™) in theformulation.25 The nasal spray demonstrated enhanced nasal
absorption of epinephrine. Even at an IN dose as low as 1 mg,

Intranasal epinephrine pharmacokinetics
the absorption was comparable to that of an IM dose of 0.3
mg, and absorption occurred more rapidly,26,27 suggesting
the potentially important role of absorption enhancers infacilitating transmucosal delivery of epinephrine.

Conclusion

Epinephrine can be significantly absorbed via the IN
route in humans. IN administration of epinephrine seemed
to be feasible, less invasive, and not associated with serious
adverse effects. Although the bioavailability of IN epinephrine
5 mg was not statistically different from that of IM epinephrine 0.3 mg, the amount of epinephrine absorption via IN
was about 0.5-fold that via IM. In addition, high variability
in IN absorption among subjects was observed with about
one-thirds of them showing poor nasal absorption. Thus,
further studies are needed for IN epinephrine administrationto achieve an adequate and consistent systemic absorption
comparable to that of the conventional IM injection.

Acknowledgments

The project was supported by funding from Siriraj
Research and Development Fund of the Faculty of Medicine
Siriraj Hospital and Prasert Prasartthongosot’s Fund of theMedical Society of Thailand. C.S., S.C. and W.C. were supported by the Chalermphrakiat Grant, Faculty of Medicine
Siriraj Hospital, Mahidol University. We would like to thank
Kevin P. Jones for English language editing of the manuscript.

Conflict of interest

The authors declared no potential conflicts of interest withrespect to the research, authorship, and/or publication of thisarticle.

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