JPT-07069; No of Pages 9

Pharmacology & Therapeutics xxx (2017) xxx–xxx

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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

The clinical pharmacology of non-sedating antihistamines

Kazuhiko Yanai a,b, Takeo Yoshikawa a,⁎, Ai Yanai a, Tadaho Nakamura c, Tomomitsu Iida a,
Rob Leurs d, Manabu Tashiro b
a
Department of Pharmacology, Tohoku University School of Medicine, Sendai 980-8575, Japan
b
Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578, Japan
c
Department of Pharmacology, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan
d
Amsterdam Institute of Molecules, Medicines and Systems, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, The Netherlands

a r t i c l e i n f o a b s t r a c t

Keywords: We previously reported on brain H1 receptor occupancy measurements of antihistamines in human brain using
Histamine [11C]doxepin and positron emission tomography (PET). We proposed the use of brain H1 receptor occupancy to
Non-sedating antihistamines classify antihistamines objectively into three categories of sedating, less-sedating, and non-sedating antihista-
PET mines according to their sedative effects. Non-sedating antihistamines are recommended for the treatment of al-
Histamine H1 receptor occupancy
lergies such as pollinosis and atopic dermatitis because of their low penetration into the central nervous system.
CNS
Physicians and pharmacists are responsible for fully educating patients about the risks of sedating antihistamines
Carnosine
Histidine
from pharmacological points of view. If a sedating antihistamine must be prescribed, its sedative effects should be
Sedation thoroughly considered before choosing the drug. Non-sedating antihistamines should be preferentially used
Impaired performance whenever possible as most antihistamines are equally efficacious, while adverse effects of sedating antihista-
P-glycoprotein mines can be serious. This review summarizes the pharmacological properties of clinically useful non-sedating
antihistamines from the perspective of histamine function in the CNS.
© 2017 Published by Elsevier Inc.

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Histamine as a “good” substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Development of non-sedating antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. PET evaluation of sedating action of antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. P-glycoprotein inhibitors and multidrug-resistance genes (MDR) gene expression . . . . . . . . . . . . . . . . 0
6. Clinical pharmacology of non-sedating antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Author disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction who developed H1 and H2 receptor antagonists, received the Nobel

Since histamine activity was discovered in 1910 by Sir Henry Dale, a
Nobel Prize winner in physiology or medicine 1936, a great number of
researchers have investigated the physiological and pathological activi-
ties of histamine. Furthermore, Daniel Bovet and Sir James W. Black,
⁎ Corresponding author at: Department of Pharmacology, Tohoku University School of
Medicine, 2-1 Seiryo-cho, Aoba-Ku, Sendai 980-8575, Japan.
E-mail address: tyoshikawa@med.tohoku.ac.jp (T. Yoshikawa).
Prize in physiology or medicine in 1957 and 1988, respectively, for mak-
ing a significant contribution to mankind. As part of recent progress in
the study of histamine, H3 and H4 receptors have been actively investi-
gated (Brioni, Esbenshade, Garrison, Bitner, & Cowart, 2011; Passani &
Blandina, 2011). To aid this research, genetic knockout mice have
been created for H1–H4 receptors, histidine decarboxylase (HDC), and
histamine N-methyltransferase (HNMT). X-ray analysis of the H1 recep-
tor has been also reported. While histamine was considered detrimental
as an allergy-causing substance, recent studies have demonstrated that

http://dx.doi.org/10.1016/j.pharmthera.2017.04.004
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2 K. Yanai et al. / Pharmacology & Therapeutics xxx (2017) xxx–xxx
Fig. 1. Carnosine–histidine–histamine pathway. The decarboxylation of L-histidine, one of
essential amino acids, is catalyzed by histidine decarboxylase (HDC), a pyridoxal
phosphate-containing enzyme (3). The dipeptide, carnosine, is synthesized by carnosine
synthetase (2) and degraded by carnosinase (1). Histamine is an important
neurotransmitter in the eye of Dorsophila, and it is inactivated by carcinine synthetase
(4), which converts to carcinine, a β-alanyl derivative (Chaturvedi, Luan, Guo, & Li,
2016). Carcinine synthetase does not exist in humans, and the function of carcinine is
poorly understood at present in humans.
physiological activities of histamine are often beneficial to the human
body. In the central nervous system, in particular, histamine plays an
important role in maintaining wakefulness and suppressing appetite.
Accordingly, the guidelines for pollinosis, atopic dermatitis, and other
allergic disease now recommend non-sedating antihistamines with
lesser penetrability into the central nervous system.
2. Histamine as a “good” substance
Histamine is a biogenic amine synthesized from the amino acid L-
histidine by histidine decarboxylase (HDC). The various biological func-
tions occur via four G protein–coupled receptor (GPCR) subtypes: H1 re-
ceptor, H2 receptor, H3 receptor, and H4 receptor (Panula et al., 2015).
The main histamine-producing cells are histaminergic neurons, the
cell bodies of which lie in the hypothalamic tuberomammillary nucleus,
gastric enterochromaffin-like (ECL) cells, mast cells, and basophils
(Falus, Grossman, & Darvas, 2004). Gastric ECL cells release histamine
Fig. 2. Synthesis of carnosine in the muscle and its activities. Carnosine (β-alanyl-L-histidine) is a dipeptide produced in muscle by condensation of histidine and β-alanine (an amino acid
that is not a constituent of protein). When β-alanine is ingested, carnosine is synthesized in the muscle (Blancquaert et al., 2015), and (1) buffering of intracellular H+ in muscle, (2 & 4)
chelating of intracellular Ca2+ and Cu2+, and (3) antioxidative action against reactive oxygen species (ROS) occur. Carnosine can be released from muscle into the circulation, and it can
activate the histaminergic neuron system, which is very similar to histidine-induced actions.
Please cite this article as: Yanai, K., et al., The clinical pharmacology of non-sedating antihistamines, Pharmacology & Therapeutics (2017), http://
dx.doi.org/10.1016/j.pharmthera.2017.04.004
upon stimulation by gastrin and acetylcholine. Through the effect of his-
tamine on histamine H2 receptors, gastric acid is secreted from parietal
cells. Mast cells and basophils store histamine within granules, and de-
granulation occurs upon stimulation by an antigen in a sensitized state.
Meanwhile, histamine contained in foods is also important. In relation
to food-derived histamine, histamine food poisoning has long been rec-
ognized in humans (Sarkadi, 2004; Visciano, Schirone, Tofalo, & Suzzi,
2014). Upon proliferation of HDC-producing bacteria, considerable
amounts of histamine may be synthesized from histidine contained in
fish. The symptoms of histamine food poisoning include urticaria, hypo-
tension, nausea, vomiting, abdominal pain, diarrhea, headache, facial
flush, and skin eruptions. The majority of symptoms develop within
one hour of eating. On the other hand, exogenously administered hista-
mine is sometimes beneficial for us. Histamine itself has been approved
for use in European countries and Israel to prevent relapse in acute my-
eloid leukemia. In accordance with this, mice with histamine deficiency
due to genetic disruption of HDC showed a high rate of colon and skin
carcinogenesis. The absence of histamine formation caused accumula-
tion of immature myeloid cells, which was accompanied by an in-
creased susceptibility to chemically induced cancer (Yang et al., 2011).
The amount of histidine contained in fish meat is greater than that of
any other essential amino acid (http://wholefoodcatalog.info/). In the
living body, levels of carnosine, histidine, and histamine are considered
to be interactively and closely correlated (Fig. 1). Carnosine, an imidaz-
ole dipeptide, has recently drawn attention for therapeutic potential in
stress- and age-related disorders (Babizhayev, 2014; Boldyrev, Aldini,
& Derave, 2013; Cararo, Streck, Schuck, & Ferreira Gda, 2015; Hipkiss,
2015). In addition to being synthesized from L-histidine by HDC, hista-
minergic neurons, in particular, contain carnosinase, and histamine
can be efficiently synthesized from carnosine (Otani, Okumura, Nagai,
& Okumura, 2008). During exercise, carnosine is synthesized from histi-
dine and β-alanine in muscle (Blancquaert, Everaert, & Derave, 2015;
Hoffman, Stout, Harris, & Moran, 2015). It has been proposed that
after being released from muscle, carnosine can stimulate central hista-
minergic neurons as shown in Fig. 2. Exercise is very effective in
preventing dementia, as demonstrated by a number of epidemiolog-
ical studies; however, the molecular mechanism underlying this
phenomenon is unknown. Carnosine is efficiently incorporated into
histamine neurons in the brain and reported to reduce the cytotoxic-
ity owing to amyloid β protein and suppresses its deposition (Corona
et al., 2011). The activities of carnosine and histidine, both of which
have the same imidazole skeleton, are as follows: antioxidant,
metal chelating (Ca2 +, Zn2 +, and Cu2 +) inside and outside the cell,
pH buffering activity (Boldyrev et al., 2013; Swietach, Leem,
Spitzer, & Vaughan-Jones, 2014), and histamine neuron-activating
effects (Shen et al., 2007).
 K. Yanai et al. / Pharmacology & Therapeutics xxx (2017) xxx–xxx 3

The central histaminergic neuron system, with cell bodies located in
the hypothalamus, constitutes one of the neuronal monoaminergic sys-
tems (Haas & Panula, 2003; Haas, Sergeeva, & Selbach, 2008; Watanabe
& Wada, 1991). Their neural fibers are extensively distributed through-
out the brain and part of the spinal cord. These neurons are strongly ex-
cited in the awakening state and release histamine. Histamine then
intensely promotes cerebral cortex function directly via H1 and H2 re-
ceptors, excitation of cholinergic and noradrenergic neurons in the
brain stem, cholinergic neurons in the substantia innominate, and
glutaminergic neurons in the thalamus. Cerebrocortical activation by
histamine is very high and closely related to maintenance of wakeful-
ness (Shan, Dauvilliers, & Siegel, 2015), promotion of cognitive function,
and suppression of appetite and stress (Watanabe & Yanai, 2001).
Therefore, when a highly brain-penetrable first-generation antihista-
mine is administered, the level of wakefulness drops, learning/memory
levels fall, and body weight increases owing to cerebrocortical inhibi-
tion (Yanai & Tashiro, 2007). Pharmacoepidemiological studies have re-
ported that first-generation antihistamine drugs increase the incidence
of dementia (Gray et al., 2015). There are several lines of evidence that
brain histamine is implicated in Alzheimer's disease. For example, both
of the brain HDC and the histidine concentration in cerebrospinal fluid
were decreased significantly in Alzheimer disease (Fonteh, Harrington,
Tsai, Liao, & Harrington, 2007; Schneider et al., 1997). In addition, sever-
al N-methyl-D-aspartate (NMDA)-receptor antagonists including
memantine, which is often used for the treatment of Alzheimer's dis-
ease, enhanced histamine neuron activity in rodents (Motawaj,
Burban, Davenas, & Arrang, 2011). A possible beneficial effect of hista-
mine-related drugs on Alzheimer's disease might not be solely due to
a simple symptomatic relief of cognitive symptoms, but could also be
the consequence of disease modifying actions (Zlomuzica et al., 2016).
From this perspective, non-sedating antihistamines are clinically supe-
rior, as central histamine activities are not suppressed (Church et al.,
2010; Holgate et al., 2003; Yanai et al., 2011).
First-generation antihistamines including mepyramine, hydroxizine,
diphenhydramine, chlorpheniramine, and promethazine were developed
between the 1940s and 1970s. Between 1980 and 1990, astemizole,
terfenadine, loratadine, epinastine, olopatadine, and ebastine were devel-
oped as parent compounds for the second-generation antihistamines.
However, astemizole and terfenadine had an ECG QT-prolonging action
through the blockade of HERG1 K+ channels, inducing severe arrhyth-
mias on rare occasions, and these were removed from the market
(Leurs, Church, & Taglialatela, 2002). The major metabolites of the sec-
ond-generation antihistamine parent compounds such as loratadine and
terfenadine are safe and efficacious with neither cardiotoxicity nor CNS
effects, and are therefore used desloratadine and fexofenadine, respec-
tively, as non-sedating antihistamines.
After 2000, levocetirizine and bepotastine were developed by
isolating optical isomers from the second-generation antihistamines.
(S)-Bepotastine and (R)-levocetirizine are carboxyl group-containing
non-sedating antihistamines, and the optical isomers with three-
dimensional structures and stronger binding affinity (potency) are
used for clinical purposes (Gillard, Van Der Perren, Moguilevsky,
Massingham, & Chatelain, 2002). Fig. 3 shows the difference in the effect
of (S)-bepotastine and (R)-bepotastine on histamine-induced skin dye
leakage (Narita et al., 1997; Ueno, Inagaki, Nagai, & Koda, 1998).
Pharmacologically speaking, it is desirable to develop a drug that does
not contain optical isomers of different potencies.

3. Development of non-sedating antihistamines

Antihistamines have been used for treating allergy since the 1940s
(Simons & Simons, 2011). The first antihistamine that is toxic to humans
was synthesized in 1937 by Italian pharmacologists Daniel Bovet and
Anne-Marie Staub. Pyrilamine, which was discovered after screening a
number of compounds, was first administered to humans in 1944. Even
today, pyrilamine (also named mepyramine) is used in basic research as
a standard H1 antagonist. First-generation antihistamines such as
pyrilamine and promethazine became prototypes for many central ner-
vous system drugs such as antipsychotics and antidepressants. In fact,
some antidepressants and antipsychotic drugs are among the most potent
H1 antagonists (Kanba & Richelson, 1991; Sato et al., 2013, 2015).
While the classical first-generation antihistamines were effective
against allergic disease, they had the drawback of a strong sedating ef-
fect due to their passage through the blood–brain barrier. Sedative ad-
verse reactions include drowsiness (emotional experience) and
impaired performance (emotional expression). Further, due to poor se-
lectivity for H1 receptors, the incidence of anticholinergic adverse reac-
tions such as dry mouth, anuresis, and tachycardia is high (Simons &
Simons, 2011; Yanai, 2012). Therefore, the utility of the first-generation
sedating antihistamines for allergic disease is limited. Aiming to over-
come these major defects, the second-generation antihistamines were
developed with high H1 receptor selectivity, low brain penetrability,
and long plasma half-life. Due to the introduction of a hydrophilic func-
Fig. 3. Differences in pharmacological actions on histamine-induced skin dye leakage
tional group (\\COOH or\\NH2), the second-generation non-sedating between bepotastine optical isomers. The data show the mean ± SEM of leaked dye
antihistamines are less likely to pass the blood-brain barrier, and intensity in 5 rats (Narita et al., 1997). Oral formulations of (S)bepotastine have been
cause a lower incidence of sedation (Yanai et al., 2011). In particular, approved by the Japanese regulatory agency in July 2000, and (S)bepotastine was also
the introduction of the COOH group is important for the non-sedating reformulated for its topical use in the treatment of allergic conjunctivitis in the USA.
Treatment of allergic conjunctivitis with non-sedating (S)bepotastine ophthalmic
properties of antihistamines because this gives rise to so-called zwitter- solution is one of effective anti-allergic medications that provides rapid and sustained
ionic” compounds, positive and negative charges in the same molecule, reduction of ocular itching and other allergy-associated ocular symptoms (Bergmann,
which can explain poor BBB penetration. Williams, & Gomes, 2014).

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4 K. Yanai et al. / Pharmacology & Therapeutics xxx (2017) xxx–xxx

Fig. 4 shows clinically used carboxyl group-containing and amino

group-containing non-sedating antihistamines, which are also consid-
ered as zwitterionic and non-zwitterionic antihistamines, respectively.
The second-generation antihistamines have stronger anti-inflammatory
actions, while clinical efficacy is almost equal between the first-genera-
tion and second-generation antihistamines. In addition, cardiovascular
adverse reactions, anticholinergic activity, and sedative properties are
rarely observed with the major carboxyl-containing second-generation
metabolites. Amino group-containing compounds such as mequitazine,
epinastine, and desloratadine have lower specificity for H1 receptors
and may block other receptors (e.g., muscarinic receptors). Ebastine
and loratadine are prodrugs that become active in the body through
conversion to carboxyl group-containing (carebastine) and amino
group-containing compounds (desloratadine), respectively.
Carboxyl group-containing antihistamines are zwitterionic, contain-
ing N+ and COO−, and exhibit high specificity for H1 receptors.
Shimamura et al. (2011) recently reported the crystal structure of
human histamine H1 receptor complex with doxepin and binding
models of zwitterionic non-sedating antihistamines. The H1 receptor
structure significantly improved understanding of high H1 receptor se-
lectivity of carboxyl group-containing antihistamines. Fig. 5 shows the
binding modes of bilastine and fexofenadine with H1 receptor by
docking simulation (unpublished data). A docking model of bilastine-
H1 receptor complex was obtained by energy minimization in the
same manner as for fexofenadine using the initial model based on the
assumption that bilastine and fexofenadine have the common
pharmacophore. These results show bilastine and fexofenadine are as-
sumed to bind in a similar mode to H1 receptor.
In general, the brain penetration depends on the concentration gra-
dient, hydrophilic properties, molecular size, and charge, if the molecule
has a net charge at physiological pH. Other determining factors of non-
sedating antihistamines include P-glycoprotein, cytochrome P450 en-
zymes, enantiomers and pKa (acid dissociation constant). In particular,
non-sedating antihistamines have a high affinity for P-glycoprotein,
while the classical antihistamines are not the substrates (Hu, Sieck, &
Hsu, 2015). Multiple factors may contribute to the penetration through
blood-brain barrier.

4. PET evaluation of sedating action of antihistamines

Fig. 4. Carboxyl group-containing zwitterionic (A) and amino group-containing non-
zwitterionic (B) antihistamines. * indicates asymmetric carbon related to optical First- and second-generation antihistamines are generally classified
isomerism. # indicates a double bond relevant to a cis-trans isomer, which is not an into sedating and non-sedating compounds based on the presence/ab-
optical isomer, but a geometric isomer with a different three-dimensional structure. $
sence of sedation. Sedating action is usually evaluated on the basis of
indicates a prodrug that is converted to its active metabolite in the body.
subjective drowsiness and impaired performance, as measured by a

Fig. 5. Interactions of bilastine and fexofenadine with the H1 ligand-binding pocket. Docking simulation of bilastine-H1 receptor complex was performed by Discovery Studio 2016 with
CHARMm force field (Dassault Systèmes, Cedex, France). Crystal structure of doxepin-H1 receptor complex from Protein data bank accession number 3RZE (Shimamura et al., 2011) was
used as a template structure. (A) Predicted binding mode of bilastine with H1 receptor. Bilastine is shown as ball and stick model with carbon atoms colored magenta, oxygens red, and
nitrogens blue. H1 receptor (green) and selected residues are shown as ribbon model and stick models, respectively. Hydrogen bonds are represented by thin lines (yellow). (B)
Superposition of bilastine (pink) and fexofenadine (cyan) in the active site. (C) Chemical structures and pharmacophore model of bilastine and fexofenadine. Roman numbers in (B)
and (C) show corresponding parts of each compound. Bilastine and fexofenadine are assumed to bind in the similar mode to H1 receptor. (For interpretation of the references to color
in this figure legend, the reader is referred to the web version of this article.)

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 K. Yanai et al. / Pharmacology & Therapeutics xxx (2017) xxx–xxx 5

cognitive function test. We have devised a method to non-invasively
quantify brain H1 receptor density, using [11C]doxepin and PET. Using
this method, we evaluated the sedating action of antihistamines by
measuring cerebral histamine H1 receptor occupancy after single-dose
administration of antihistamine (Yanai et al., 2016). After placebo/anti-
histamine is taken by healthy young males (20–30 years old), [11C]
doxepin is administered at Tmax, and cerebral H1 receptor occupancy is
measured. More than one week later, the second [11C] doxepin PET
scan is performed after the administration antihistamine/placebo in
the same subject. There are gender differences between males and fe-
males in cerebral H1 receptor findings on PET (Yoshizawa et al., 2009)
as shown in Fig. 6. In addition, H1 receptor binding markedly decreased
with age (Higuchi et al., 2000). Therefore, the sample population was
restricted to healthy young males in our PET studies.
Cerebral H1 receptor occupancy was at least 50% after single-dose
administration of a first-generation antihistamine, with a high inci-
dence of drowsiness and impaired performance (Okamura et al.,
2000). In contrast, the occupancy rate was around 20% or below for sec-
ond-generation antihistamines (Fig. 7). We classified the sedating effect
of antihistamines, based on cerebral H1 receptor occupancy after single-
dose administration, into sedating (≥50%), less sedating (50–20%), and
non-sedating (b 20%) groups. As for the relationship between cerebral
H1 receptor occupancy and drowsiness/impaired performance, im-
paired performance was more frequently observed with statistical sig-
nificance when cerebral H1 receptor occupancy was 20% or higher. In
the case of a completely non-sedating antihistamine such as
fexofenadine, H1 receptor occupancy did not increase with a higher
dose of the drug. In fact, fexofenadine and bilastine do not penetrate
the BBB at all and, consequently, have no H1 receptor occupancy
(Farré et al., 2014; Hiraoka et al., 2015).
It is known that the sedating effect of antihistamines varies among
individuals. As H1 receptor genetic polymorphism does not frequently
occur, it is difficult to explain the inter-individual difference in drowsi-
ness by polymorphism. Therefore, inter-individual differences could

Fig. 6. Gender difference in H1 receptors in the human brain. Twelve healthy normal female volunteers (age 22.3 ± 2.5, weight 50.3 ± 3.7 kg, BMI 20.3 ± 1.7; mean ± SD) and 12 healthy
normal male volunteers (age 21.8 ± 1.2, weight 62.0 ± 4.8 kg, BMI 20.6 ± 1.8; mean ± SD) were examined using [11C]doxepin. The averaged and normalized PET images in female (A) and
male (B) subjects are illustrated as the binding potential (Bmax/Kd) of H1 receptors. Female subjects have significantly higher binding potential of [11C]doxepin to H1 receptors in the
cerebral cortical areas than male volunteers. Sexual dimorphism on brain histamine system was reported previously in animal studies (Ferretti et al., 1998; Ghi, Orsetti, Gamalero, &
Ferretti, 1999).

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6 K. Yanai et al. / Pharmacology & Therapeutics xxx (2017) xxx–xxx

be explained in terms of H1 receptor occupancy or differences/changes
in sensitivity to subjective experiences. In order to decrease the report-
ed bias, all published reports on placebo-controlled randomized double-
blind studies of drowsiness and impaired performance induced by anti-
histamines were precisely analyzed by research groups of University of
Surrey (Hindmarch, 2009; McDonald, Trick, & Boyle, 2008; Shamsi &
Hindmarch, 2000). They then proposed the incidence of sedation scored
as proportional impairment ratio (PIR) for each antihistamine from sub-
jective and objective perspectives. PIR was mostly correlated to H1 re-
ceptor occupancy rate on PET (The inset in Fig. 7). Both values of
cerebral H1 receptor occupancy and PIR were sequential without any
clear non-sedating cutoff values.
Considering the increase in allergy patients, appropriate use of fast-
acting antihistamines is important. However, sufficient consensus has
not yet been reached on the characteristics of ideal antihistamines.
CONGA (Consensus Group of New Generation of Antihistamines), an ex-
pert committee, was launched to examine the subject, and criteria for
ideal antihistamines were proposed (Holgate et al., 2003). Classification
of sedating actions based on H1 receptor occupancy was adopted. In the
atopic dermatitis treatment guideline recently issued by the Japanese
Dermatological Association, standards for “non-sedating antihista-
mines” were established for the first time in Japan, and classification
based on H1 receptor occupancy was introduced. Even in cases where
impaired performance is definitely observed, the patient is often not
conscious of drowsiness. Therefore, the sedating action of antihista-
mines should be assessed by cerebral H1 receptor occupancy on PET,
rather than by subjective drowsiness or difficult-to-detect impaired
performance (Hindmarch, 2009).
Our doxepin-PET study demonstrated that about 50% of cerebral H1
receptors were occupied even 12 h after the use of a sedating
antihistamine at night (Zhang et al., 2010), and that about 50% of cere-
bral H1 receptors were occupied even after the use of sedating antihista-
mine-containing eye drops (Yanai et al., 2016). The cerebral half-life of
sedating antihistamines such as diphenhydramine is at least 30 h, which
is much longer than plasma half-life (Yanai et al., 2016). In fact, when a
sedating antihistamine is used as a sleep inducer at night, there may be a
risk of medication hangover the next day (Church et al., 2010).
Furthermore, topical administration of sedating antihistamines to the
eye or nasal mucosa results in a great number of cerebral H1 receptors
being occupied due to the absence of a first-pass effect. Therefore,
non-sedating antihistamine-containing eye or nasal drops should be
used as first choice treatments.
We propose a method to assess sedating action by measuring H1 re-
ceptor occupancy after single-dose administration. The weakness of this
method is that the measurement is not made in allergy patients after
multiple dosing. In order to carry out PET measurement twice, multiple
dosing needs to be conducted in the same subjects, which is not a simple
procedure. A study has actually been carried out to measure H1 receptor
occupancy in patients with mild allergy after single and consecutive
dosing with the non-sedative antihistamine olopatadine (Senda et al.,
2009). The finding was that receptor occupancy after consecutive dos-
ing (about 45%) was higher than the level after single-dose administra-
tion (about 15%). H1 receptor occupancy may possibly increase when
repeatedly administering some drugs classified as non-sedating antihis-
tamines. H1 receptor occupancy should be measured and compared be-
tween single and consecutive dosing for fexofenadine or bilastine,
completely non-sedating antihistamines exhibiting almost no H1 recep-
tor occupancy.
5. P-glycoprotein inhibitors and multidrug-resistance genes (MDR)
gene expression
One possible explanation for non-sedative properties is the
efflux function of p-glycoprotein through blood-brain barrier. A
human study using functional MRI and cognitive studies showed
increased sedation during the combination cetirizine and verapamil
(Conen et al., 2013). In our preliminary study, we examined the influ-
ence of p-glycoprotein on non-sedating antihistamines in mice and
humans using different methods (Fig. 8). As cetirizine is a racemic mix-
ture of levocetirizine and dextrocetirizine, we examined the brain to
blood ratio of [11C]verapamil as an index of substrate of P-glycoprotein
after treatment of levocetirizine and dextrocetirizine (Iida et al., 2012;
Ishiwata, Kawamura, Yanai, & Hendrikse, 2007). Both isomers did not
have any significant effects on the uptake [11C]verapamil in the mouse

Fig. 7. Classification of antihistamines by H1 receptor occupancy and sedating actions after single-dose administration. This is a summary of measurements of H1 receptor occupancies after
antihistamine administration using [11C] doxepin-PET by our and other research groups. The data are represented as the mean ± SD. When H1 receptor occupancy was 20% or lower,
impaired performance was not observed in a simultaneously performed cognitive function test (Okamura et al., 2000; Tashiro et al., 2004), and therefore, the drug could be classified
as “non-sedating.” As shown in the inset right, the incidence of sedation (PIR) obtained by a literature search (McDonald et al., 2008) is well-correlated with H1 receptor occupancy.
The lower H1 receptor occupancy, the lower was PIR.

Please cite this article as: Yanai, K., et al., The clinical pharmacology of non-sedating antihistamines, Pharmacology & Therapeutics (2017), http://
dx.doi.org/10.1016/j.pharmthera.2017.04.004
 K. Yanai et al. / Pharmacology & Therapeutics xxx (2017) xxx–xxx 7

brain (Fig. 8A). In contrast, cyclosporine A, a strong inhibitor of p-glyco-
protein, significantly increased the uptake [11C]verapamil in the mouse
brain. As species difference has been observed as a substrate of P-glyco-
protein (Wang, Casciano, Clement, & Johnson, 2001), further studies are
warranted to clarify the actual role of p-glycoprotein inhibitors on the
brain penetration of non-sedating antihistamines in humans.
The efflux of fexofenadine by P-glycoprotein is not as remarkable as
loratadine and cetirizine (Obradovic, Dobson, Shingaki, Kungu, &
Hidalgo, 2007), even though the H1 receptor occupancy of fexofenadine
is nearly zero in humans. A previous report suggested that the high pKa
of fexofenadine played an important role in the membrane permeability
(Kikuchi, Nozawa, Wakasawa, Maeda, & Tamai, 2006). The high concen-
tration of ionized form of fexofenadine at physiological pH might inhibit
the brain penetration in humans. The plasma concentrations of
fexofenadine after a single oral administration were lower in persons
with 2677AA/3435CC genotype of MDR1 than in persons with other ge-
notypes (Yi et al., 2004). In contrast, the function of P-glycoprotein at
the blood-brain barrier measured by the brain uptake of [11C]verapamil
was not different between the haplotypes of 3 single nucleotide poly-
morphisms (C1236T, G2677T, and C3435T) of MDR1 gene (Takano et
al., 2006). We also did not observe any significant correlation of a poly-
morphism in C3435T of MDR-1 with the H1 receptor occupancy by
fexofenadine (unpublished data), although a tendency of lower brain
penetration of fexofenadine exists in persons with 3435CC genotype
(Fig. 8B). These studies suggested the MDR gene expression might not
have any considerable effects on the H1 receptor occupancy in humans.
6. Clinical pharmacology of non-sedating antihistamines
6.1. Constitutive activity
Many international guidelines recommend non-sedating antihista-
mines as the first choice for treating allergic diseases (Magerl et al.,
2016; Zuberbier et al., 2006, 2014). While GPCR-mediated signal trans-
mission was originally considered to be possible only after agonist bind-
ing, recent findings suggest that H1 receptor responses can be
transmitted when a great number of histamine H1 receptors are
expressed, even in the absence of the agonist histamine. Such a state
of histamine receptor activation in the absence of histamine is called
constitutive activity. Antihistamines act as inverse agonists on constitu-
tively active H1 receptors, rendering activated histamine H1 receptors
inactive (Leurs et al., 2002; Monczor, Fernandez, Fitzsimons, Shayo, &
Davio, 2013). In allergic individuals, allergic responses are transmitted
even without histamine release from mast cells, and therefore, treat-
ment with antihistamines is initiated before the pollinosis season be-
gins. This is with the aim of suppressing allergic activity, presumably
not by directly blocking histamine activity, but by restraining constitu-
tive activity. From this perspective, long-term use of non-sedating anti-
histamines in monthly regimens is desirable as adverse reactions are
uncommon (Grob, Auquier, Dreyfus, & Ortonne, 2009). Carboxyl
group-containing non-sedating antihistamines are particularly suitable
for long-term use due to their reduced anticholinergic activity.
6.2. Potency and efficacy
Binding affinity (potency) to H1 receptors is substantially different
among antihistamines (Yanai et al., 2011). More than a hundredfold dif-
ference exists in binding affinity (potency) among various antihista-
mines. Based on potency, non-sedating antihistamines can be
classified into low- (loratadine, fexofenadine) and high-potency groups
(bepotastine, olopatadine, cetirizine, epinastine, levocetirizine). How-
ever, though potency varies greatly among antihistamines, clinical effi-
cacy as represented by maximum responsiveness is the same if
administered in sufficient dosages. For this reason, it is desirable to in-
crease the dosage of carboxyl group-containing non-sedating antihista-
mines if efficacy is insufficient. As the pharmacokinetics of non-sedating
antihistamines are very different among individuals, a fixed dosage may
not produce the specified efficacy. The latest guidelines recommend
that the dosage of non-sedating antihistamines can be increased by 2–
4 times when efficacy is insufficient (Zuberbier et al., 2006, 2014). Car-
boxyl group-containing non-sedating antihistamines with no anticho-
linergic action are suitable for dose increases.
6.3. Pediatric use
Caution is advised in administering sedating antihistamines for chil-
dren. The incidence of sedative effects is even higher in children, and
their learning ability may be reduced. As estimated from animal exper-
imental data, administration of sedating antihistamines is likely to in-
duce convulsions in children with a convulsive predisposition. They
also increase the risk of obesity through central H1 receptor blockade
(Kim, Huang, Snowman, Teuscher, & Snyder, 2007; Masaki &
Yoshimatsu, 2006). In a small-scale observational study in children, fe-
brile convulsion worsened with the use of a sedating antihistamine
(Zolaly, 2012). The regulatory agency advised the discontinuation of
OTC cold medicines containing sedating antihistamines for children

Fig. 8. Effects of p-glycoprotein on the brain penetration of non-sedating antihistamines in mice (A) and humans (B). Brain penetration of non-sedating antihistamines in mice were
analyzed using [11C]verapamil in vivo (A). Levocetirizine (10 mg/kg, PO), dextrocetirizine (10 mg/kg, PO), cyclosporine A (CsA)(50 mg/kg, IV) and saline were administered to mice
(each group = 6–8) before the intravenous injection of [11C]verapamil, a substrate of p-glycoprotein. At 15 min, the mice were sacrificed and the radioactivity of brain and blood was
measured. One-way ANOVA Dunnett's multiple comparison shows insignificant effects of levo- and dextro-cetirizine on [11C]verapamil penetration in vivo. In contrast, cyclosporine A
has significant effects as a positive control vs. saline and cetirizine groups (P b 0.01). (B) We analyzed the MDR-1 sequence in 24 volunteers whose H1 receptor occupancy had been
determined after orally administered fexofenadine (Tashiro et al., 2004). Insignificant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with the H1 receptor occupancy
by fexofenadine was observed. The data are represented as the mean ± SD.

Please cite this article as: Yanai, K., et al., The clinical pharmacology of non-sedating antihistamines, Pharmacology & Therapeutics (2017), http://
dx.doi.org/10.1016/j.pharmthera.2017.04.004
8 K. Yanai et al. / Pharmacology & Therapeutics xxx (2017) xxx–xxx
under 2 years of age. Accordingly, pharmaceutical companies have vol-
untarily recalled such medicines. After a voluntary market withdrawal
and labeling revision, emergency department visits for adverse drug
events due to cough and cold medicine declined among children aged
b2 years and 2 to 3 years (Hampton, Nguyen, Edwards, & Budnitz,
2013; Shehab, Schaefer, Kegler, & Budnitz, 2010). As the efficacy of
non-sedating antihistamines has proven in pediatric allergic diseases
(Warner, 2001), non-sedating antihistamines should also be the first
choice for pediatric allergy.
7. Conclusion
The release of histamine and its many effects on target cells contrib-
utes to the acute and chronic symptomatology characteristic of allergy
disorders. Blockade of this receptor provides a highly successful ap-
proach to controlling allergic symptoms. The second-generation anti-
histamines can be so called “non-sedating antihistamines” because of
the lack of penetration through the blood–brain barrier. The pharmaco-
logical properties of clinically useful non-sedating antihistamines are
described in detail in terms of the recent advance of histamine research.
Author disclosure
The authors (Drs. Tashiro M and Yanai K) received research grants
from GlaxoSmithKline Japan, on PET and cognitive human studies on
levocetirizine. In the last 3 years, Yanai K had received lecture honoraria
from manufactures of 2nd generation antihistamines, including Sanofi,
GlaxoSmithKline, Kyowa-Kirin, Taiho and Mitsubishi Tanabe Pharma-
ceutical Co. Ltd. Other authors have no conflict of interest. Decisions re-
garding all aspects of the review were made by all authors without
consulting with pharmaceutical companies.
Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific Re-
search (#26253016 and #26670117) from the Japan Society for Promo-
tion of Science (JSPS). We appreciate Dr. Takashi Watanabe (Chief
Researcher, Medicinal Chemistry Laboratory, Pharmaceutical Research
Center, Meiji Seika Pharma Co., Ltd.) for discussing the manuscript on
the model simulation between H1 receptor and non-sedating
antihistamines.
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