Clinical and Experimental Allergy, 1999, Volume 29, Supplement 3, pages 116–124

The metabolism of antihistamines and drug interactions:

the role of cytochrome P450 enzymes
A. G. RENWICK
Clinical Pharmacology Group, University of Southampton, Southampton, UK

Summary
The non-sedating antihistamines show a diversity of fates in the body and the parent drugs
and metabolites may differ in their biological properties. Clinically significant interactions
with inhibitors of cytochrome P450 have been reported primarily for terfenadine, which has
the potential for cardiac toxicity, and is metabolized to fexofenadine, an antihistamine
without cardiac effects. Astemizole shares many of these characteristics and important
safety-related interactions are likely. Loratadine undergoes extensive metabolism so that
pharmacokinetic interactions could occur, but they would be of little clinical importance
because of the lack of cardiac activity of the parent drug and its metabolites. Ebastine also
undergoes pharmacokinetic interactions, the significance of which is dependent on clar-
ification of the extent of any relevant cardiotoxicity of both ebastine and its metabolite.
Interactions would not be clinically important for cetirizine and fexofenadine which do not
show cardiac effects and are eliminated with little metabolism.
Keywords: metabolism, cytochrome P450, pharmacokinetics, cardiotoxicity

in drug metabolism with isoenzymes of CYP2B, CYP2C,

Introduction
The second-generation antihistamines (H1 antagonists with
enhanced potency and reduced sedative effects) are lipid
soluble drugs which are rapidly and well absorbed from the
gastrointestinal tract. In common with most lipid soluble
xenobiotic chemicals, most antihistamines undergo meta-
bolism, prior to elimination from the body. Lipid soluble
drugs partition into cell membranes including the endo-
plasmic reticulum where they are oxidized by the cyto-
chrome P450 enzyme system(s).
Cytochrome P450 is a super-family of haem-containing
proteins present within the endoplasmic reticulum which
show low substrate specificity and are responsible for the
oxidation of a wide variety of lipophillic substrates, includ-
ing steroids. Cytochrome P450 reactions result in the
introduction of oxygen (derived from molecular oxygen)
into aliphatic and aromatic rings, and side chains (e.g.
methyl-, ethyl-, etc.), as well as oxidation at noncarbon
atoms such as nitrogen and sulphur. Cytochrome P450
families 1, 2 and 3 (CYP1, CYP2 and CYP3) are involved
Correspondence: Dr A. G. Renwick, Clinical Pharmacology Group,
University of Southampton, Biomedical Sciences Building, Bassett
Crescent East, Southampton SO16 7PX, UK.
116
CYP2D and CYP3A responsible for most drug oxidation
reactions.
Cytochrome P450 isoenzymes (P450s) are detectable in
most tissues but the highest concentrations of most iso-
enzymes are found in the liver; the intestinal wall is also rich
in one particular isoenzyme CYP3A4. This localization of
enzyme activity means that P450 isoenzymes may be
involved in both first-pass metabolism, which determines
the entry of drugs into the general circulation (the bioavail-
ability; F), and clearance (CL), which is the elimination
from the general circulation [1].
Following a single oral dose, the maximum drug con-
centration in plasma depends on the absorption rate (deter-
mined by the drug lipophillicity and formulation), the
apparent volume of distribution (V) (determined by lipo-
phillicity and protein binding), the bioavailability (F) and
the terminal elimination rate [determined by distribution (V)
and clearance (CL)]. The best measure of the overall body
exposure or internal dose is given by the area under the
plasma concentration–time curve (AUC). Again, P450 iso-
enzymes are critical in determining the AUC as:
Dose × F
AUC ¼
CL
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 Metabolism of antihistamines and drug interactions 117

Table 1. Metabolites of non-sedating antihistamines and their activities

Half-life Half-life of Activity of metabolites

Drug of drug (h) Enzyme Main metabolites metabolites (h) at therapeutic concentractions

Astemizole 48 CYP3A4 Desmethylastemizole 12 days Antihistamine; Kþ channel blockade

Azelastine 25* P450 Desmethylazelastine 48 Antihistamine
Cetirizine 9 None None (minor only) — None (most drug eliminated unchanged in urine)
Ebastine ND CYP3A4 Carebastine 14 Antihistamine
Fexofenadine 14 None None — None (drug eliminated unchanged in urine)
Loratadine 10 CYP3A4 þ Descarboethoxy loratadine 20 Antihistamine; inhibits cytokine production
CYP2D6
Terfenadine ND CYP3A4 Carboxylic acid analogue 4 Antihistamine

* non-specific assay used (measured parent drug and metabolite); ND ¼ not determined due to low or undetectable plasma concentrations;
compounds given in bold have been reported to block cardiac Kþ channels and/or increase QT interval in animal models: astemizole and
terfenadine have been reported to produce clinically significant increases in QT interval in humans associated with clinical cases of torsade
de pointes.

During chronic drug dosage the concentrations of drug in
the plasma and tissues build up until a steady-state is
reached in which the daily input (dosage/dose interval) is
balanced by the daily output [plasma concentration times
plasma clearance (CL)]. The average plasma concentration
at steady state (Css) is determined by:
Dose F ðbioavailabilityÞ
Css ¼ × inhibition) (Table 2).
Dose interval CL ðclearanceÞ
The essential role of P450 isoenzymes in both bioavailabil-
ity and clearance for most drugs means that the activity of
these enzymes will determine the relationship between the
external dosage regimen and Css, and also the extent of
accumulation. The plasma half-lives of most non-sedating
antihistamines and their active metabolites are less than 24 h
and so they would show limited accumulation in healthy
subjects [2]; an exception is the desmethyl metabolite of
astemizole [3] which has a half-life of about 10 days. The
half-lives and potential for accumulation of the parent drugs
would be increased by impaired hepatic oxidation due to
liver disease or drug interactions.
Any change in the activity of P450 isoenzymes may
affect profoundly the values of F and CL and therefore
may alter the peak concentration, the AUC and Css. The
consequence of any change in these values will depend on
the biological activity of the parent drug compared to the
metabolite and the direction of the change in P450 activity,
i.e. an increase (enzyme induction) or a decrease (enzyme
The cytochrome P450 isoenzymes involved in the
metabolism of antihistamines
Terfenadine is absorbed completely from the gut but under-
goes extensive first-pass metabolism. The bioavailability is
less than 0.01 and the concentrations of terfenadine in
the circulation are not detectable [4] or barely detectable
(1–4 ng/mL after 120 mg oral doses [5]). The P450 iso-
enzyme primarily involved in terfenadine metabolism is
CYP3A4 [6]; this is the principal constitutive P450 iso-
enzyme in both the liver and the intestinal wall [7] and both

Table 2. Effects of inducers and inhibitors

Toxicological consequences

Change in metabolic activity Metabolic consequences Parent compound toxic Metabolite toxic

Induction ↓ [Parent] ↓
↑ [Metabolite] ↑
Inhibition ↑ [Parent] ↑
↓ [Metabolite] ↓

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118 A. G. Renwick
sites probably contribute to the extensive first-pass metabo-
lism. The products of terfenadine metabolism are an active
carboxylic acid and an inactive carbinol. Terfenadine is
oxidized initially to azacyclonol and terfenadine alcohol,
with the latter further oxidized to azacyclonol and terfena-
dine carboxylic acid; CYP3A4 is the principal enzyme
involved in each of these reactions [6 8].
Loratadine is converted to descarboethoxyloratadine by
human liver microsomes, primarily by CYP3A4- and CYP
2D6-mediated oxidation [9]. Orphenadine appears to be
metabolized by CYP3A isoenzymes based on in vitro
studies using rat microsomes [10].
The metabolism and pharmacokinetics of CYP3A sub-
strates, such as felodipine [11] and nifedipine [12] show
very wide interindividual differences. The variability is prob-
ably due to differences in the genetic expression of the
CYP3A4 isoenzyme [13] and possibly in the expression of
minor forms such as CYP3A5 and the fetal form (CYP3A7).
The role of P-glycoprotein
Studies on the uptake of drugs by Caco-2 cells in vitro, have
indicated that P-glycoprotein (the multidrug resistance
transporter) may be important in limiting intestinal drug
absorption [14]. The transporter is on the apical side of the
brush border membrane and acts to transport molecules
actively from the cell into the intestinal lumen [15,16].
P-glycoprotein is an important transporter for the elim-
ination of drugs into the intestinal lumen [16].
There is probably a close interrelationship between
intestinal P-glycoprotein and CYP3A4, both in relation to
substrate specificity [15–17] and factors affecting their
activities [15,18]. The activities of the hepatic
CYP3A4 (rather than intestinal CYP3A4) and intestinal P-
glycoprotein both contribute significantly to interpatient
variability in the pharmacokinetics of oral cyclosporin
[19]. Terfenadine has been shown to inhibit P-glycoprotein
in vitro, but no published data have been identified on the
effect of P-glycoprotein on the pharmacokinetics of non-
sedating antihistamines, but analogy would suggest that an
interaction is likely. The antihistamines are lipid soluble
drugs and therefore they would eventually be absorbed
completely from the gastro-intestinal tract. However, for
antihistamines which are high affinity substrates for both
intestinal CYP3A4 and P-glycoprotein, following uptake by
enterocytes the drug would either be metabolized or trans-
ferred back into the gut lumen by P-glycoprotein. The drug
transferred back into the gut would then undergo passive
absorption into the enterocyte and present itself again
for metabolism or transfer out of the cell. In consequence
P-glycoprotein would not block the absorption of the drug,
but greatly increase the potential for intestinal first-pass
metabolism.
q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, Supplement 3, 116–124
Inhibition of P-glycoprotein has been reported for a
number of drugs, for example quinidine and verapamil
[20]. Inhibition of P-glycoprotein by CYP3A inhibitors,
such as erythromycin and ketoconazole which are discussed
below, may have contributed to the pharmacokinetic and
toxicological consequences detected when coadministered
with antihistamines. Inhibition of P-glycoprotein, which
also serves as an efflux transporter in the kidney [21], may
explain interactions between ‘CYP3A inhibitors’ and non-
sedating antihistamines which are absorbed and eliminated
without significant metabolism.
Cardiac side-effects of antihistamines
The clinical importance of these pharmacokinetic aspects
has been thrown into sharp focus by the adverse cardiac
effects produced by some of the second generation anti-
histamines. Both terfenadine and astemizole are associated
with cases of prolongation of the QT interval and torsade de
pointes. The overall therapeutic or toxic response to a drug
depends on two primary factors, the internal dose (as
determined by peak concentration, or AUC or Css-see
above) and the inherent sensitivity of the tissues to the
drug. Low incidences of adverse reactions may arise from
an abnormal relationship between external and internal dose
and/or an idiosyncratically exaggerated tissue response to
the drug. The adverse cardiac reactions to terfenadine
probably arise from a combination of enhanced plasma
concentrations of the parent compound, combined with an
idiosyncratic responsiveness or a predisposing sensitivity
such as cardiac disease [22].
Early antihistamines, such as promethazine, are poorly
tolerated due to sedative properties but do not show the
cardiac effects of the second generation antihistamines.
Promethazine is metabolized by CYP2D6 [23] and the
large interindividual differences in the genetic expression
of this isoform would have ensured the rapid detection of a
problem, such as torsade de pointes, without the need
for subtle interactions with other substrates or inhibitors of
P450 oxidation.
A review of the different case reports of torsades de
pointes associated with terfenadine [24] has suggested two
principal contributory factors (Table 3); firstly abnormally
high circulating levels of free terfenadine due to over-
dosage, drug interactions with CYP3A inhibitors or liver
disease [25] and one or more factors predisposing to drug-
induced torsade de points (e.g. ischaemic heart disease or a
prolonged QT interval). The importance of pharmacokinetic/
metabolic interactions was shown in the first published report
of terfenadine-induced torsade de pointes [26] which
occurred in a patient co-prescribed ketoconazole (plus
cefaclor and medroxyprogesterone), who showed elevated
plasma concentrations of terfenadine and lower levels of its

Table 3. Cardiotoxicity of antihistamines: predisposing factors in
clinical cases
Pharmacokinetic Pharmacodynamic
Overdose QT-prolongation
CYP3A4 inhibitors Cardiac disease
Cirrhosis Hypokalaemia
metabolite. Terfenadine, and to a lesser extent ebastine,
prolonged the QTc interval in anaesthetized and conscious
guinea-pigs given intravenous and oral doses [27]. This effect
was enhanced after oral dosage by pretreatment with keto-
conazole, but ECG changes were not produced by loratadine
either alone or following ketoconazole. A subsequent study
[28] indicated that ketoconazole alone significantly pro-
longed the QT interval in guinea-pigs. Comparison of the
doses associated with a significant prolongation of QTc
interval and inhibition of histamine-induced bronchocon-
striction in guinea pigs [29] showed only a 1–4-fold differ-
ence in favour of H1 antagonism for terfenadine, astemizole
and ebastine. In contrast, the corresponding oxidative
metabolites, terfenadine carboxylic acid, norastemizole and
carebastine showed antihistamine activity, but were essen-
tially devoid of cardiac effects. Although studies using
intravenous dosage of drugs which undergo essentially com-
plete first-pass metabolism are difficult to interpret, inter-
actions which inhibit first-pass metabolism will increase the
circulating concentrations of the parent drug and may
increase the risk of cardiac complications from the
parent compound, whereas interactions, such as enzyme
induction, which increase the rate of metabolism would
decrease the risk. The recent report that desmethylastemi-
zole (norastemizole) prolongs the action potential of iso-
lated rabbit ventricular myocytes [30] suggests that the
cardiac toxicity may be due to both the parent compound
and this metabolite.
Cetirizine produced antihistamine but not cardiac effects
in a guinea-pig model sensitive to the cardiac actions of
terfenadine and astemizole [29]. Thus cetirizine resembles
the carboxy-metabolite of terfenadine (fexofenadine) in its
antihistamine activity, biological fate and safety profile.
Cetirizine and fexofenadine differ from the other non-
sedative antihistamines because they are eliminated
primarily by renal excretion of the parent drug with little
metabolism [2]. In consequence the drug interactions
critical for terfenadine and astemizole would not be
relevant, and renal disease rather than liver disease could
result in elevated plasma concentrations, although increased
AUC values and longer half-lives have been reported in
patients with chronic liver disease [31]. However, cetirizine
q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, Supplement 3, 116–124
Metabolism of antihistamines and drug interactions 119
was without ECG effects even after dosage for 7 days [32],
indicating negligible risk of adverse cardiac effects.
Epinastine did not produce the ECG changes detected in
rats with terfenadine [33], but the doses of epinastine given
to rats resulted in plasma concentrations of 400 ng/ml which
is only 10 times therapeutic levels. An increased cardio-
vascular risk due to a drug interaction plus predisposing
sensitivity cannot be ruled out for this drug, based on these
animal data.
Loratadine and cetirizine do not prolong repolarization
and would not induce torsade de pointes [34].
Interactions with azole compounds
Terfenadine
The case of torsade de pointes in a patient receiving
coadministered terfenadine and ketoconazole [26] was one
of the earliest indications of the link between decreased
first-pass metabolism and adverse effects. This interaction
was studied further in six subjects given 60 mg terfenadine
twice daily for 7 days to establish steady-state conditions
and to assess plasma concentrations of terfenadine and ECG
changes. They were subsequently given ketoconazole
(200 mg every 12 h) while maintaining their terfenadine
dosage for a period of 7 days (with close monitoring for
the first 3 days) followed by further kinetic and ECG
measurements. Terfenadine was detectable in only one of
the six subjects prior to ketoconazole but in five subjects
after ketoconazole; a subject with 5 ng/ml of terfenadine in
plasma prior to ketoconazole had a peak concentration of
81 ng/ml after ketoconazole which was accompanied by
marked ECG changes. There was a clear relationship
between plasma terfenadine concentration and the change
in corrected QT interval (an effect of ketoconazole per se on
QT interval was not investigated). The plasma concen-
trations of unchanged terfenadine detected when terfenadine
was co-administered with ketoconazole were similar to
those found postmortem in a woman who had suffered a
fatal cardiac arrest (55 ng/ml) which may have resulted from
a terfenadine–ketoconazole interaction [35].
Itraconazole was also one of the first drugs to be impli-
cated in causing symptomatic torsade de pointes associated
with significant increases in plasma concentrations of
terfenadine [36]. The metabolic basis for this was demon-
strated in a clinical trial [37] in a small group of healthy
volunteers. Co-administration of itraconazole with terfen-
adine gave detectable plasma concentrations of parent drug
in most subjects and this was associated with a prolonged
QT interval. Itraconazole is an effective in vivo inhibitor of
the metabolism of CYP3A substrates such as felodipine.
The maximum plasma concentration and AUC of felodipine
were increased 6–8-fold whereas the half-life only doubled
120 A. G. Renwick
[38] which suggests that the inhibition is primarily at the
first-pass metabolism by the intestinal wall. Other reported
interactions include a loss of consciousness when terfen-
adine is taken with itraconazole [39].
In contrast, a similar study with fluconazole did not result
in measurable plasma concentrations of terfenadine or
changes in cardiac repolarization [40].
Astemizole
The plasma AUC after a single oral dose of astemizole was
increased more than 2-fold when given after a period of
14 days’ treatment with itraconazole (200 mg twice daily)
[41]. There was no measurable effect of QTc intervals, but
the long half-life of astemizole which increased from 2.1 to
3.6 days, and the potential for accumulation of astemizole
on daily dosage raises doubts about the apparently negative
single-dose observation.
Azelastine
Azelastine undergoes first-pass metabolism to a desmethyl
metabolite, which has a longer half-life in vivo [42], has
antihistamine activity and is probably responsible for much
of the activity in vivo. Blood concentrations of ‘parent þ
metabolite’ were twice as high in the elderly as in the young
[43] but formal studies on drug interactions have not been
identified.
Interactions with macrolide antibiotics
Macrolide antibiotics are recognized inhibitors of CYP3A4
[44] and therefore an interaction with terfenadine, astemi-
zole and ebastine would be predicted. Erythromycin is an
inhibitor of a number of P450 isoenzymes, as it potentiates
the effects of carbamazepine (CYP3A) and theophylline
(CYP1A/2A) [45]. Macrolide antibiotics were one of the
drug classes which were associated with the adverse cardiac
effects reported with terfenadine (see [46]). A recent review
has concluded that whereas erythromycin and clarithro-
mycin are potent inhibitors of cytochrome P450
reactions, azithromycin and dirithromycin are not inhibitors
and would not produce clinically significant interactions
[47].
Terfenadine
An interaction study [46] investigated the effect of erythro-
mycin (500 mg three times daily for 1 week) on the phar-
macokinetics of terfenadine (60 mg twice daily). Using an
assay with a limit of detection of 5 ng/ml, only three of the
nine subjects had measurable terfenadine concentrations
q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, Supplement 3, 116–124
after terfenadine þ erythromycin (11, 16 and 34 ng/ml).
Coadministration of erythromycin did not produce a sig-
nificant change in QTc interval in the six subjects studied
electrocardiographically after terfenadine þ erythromycin.
These data indicate that clinical doses of erythromycin
produce a less potent interaction than clinical doses of
ketoconazole (see above). Co-administration of terfenadine
with either erythromycin or clarithromycin resulted in
significantly altered pharmacokinetics with detectable con-
centrations of terfenadine per se in about one half of the
subjects receiving the combination [48]. Elevated concen-
trations were associated with altered cardiac repolarization;
three out of six volunteers who accumulated terfenadine
per se showed prolonged QT intervals [48]. Pretreatment
with erythromycin for 1 week [46] also increased the AUC
of the acid metabolite.
There was no effect of azithromycin on terfenadine
concentrations [48], and the plasma concentration–time
curve of the carboxy-metabolite of terfenadine was not
altered when terfenadine was co-prescribed with azithro-
mycin [49]: the absence of any effect on the QTc interval
indicates the absence of a clinically significant interaction
with azithromycin.
Co-administration of loratadine with erythromycin in 24
healthy volunteers for 10 days [50] resulted in an increase in
plasma concentrations of the parent drug and its active
metabolite (Table 1) but there was no effect on QTc inter-
vals, which is consistent with their lack of cardiac activity
in vitro.
Astemizole
Coadministration of astemizole with clinical doses of
dirithromycin in healthy volunteers resulted in a small
(34%) increase in oral AUC of a single oral dose of
astemizole (but not of its N-desmethyl-metabolite); there
was no effect on QTc intervals and this interaction was
considered not to be of clinical significance [51] despite the
long half-life of astemizole.
Interactions with other CYP3A inhibitors
An early in vivo study using cimetidine, which is a non-
specific inhibitor of cytochrome P450 isoenzymes, found no
interaction with terfenadine [52] despite the fact that it is a
good in vivo inhibitor of the metabolism of other substrates
of CYP3A, such as nifedipine [53]. Similarly, cimetidine
pretreatment did not increase the plasma concentration of
ebastine or its active metabolite [54].
Cimetidine increased the plasma concentrations of hydro-
xyzine (a first-generation antihistamine) but not of its
carboxylated metabolite cetirizine [55].
 Metabolism of antihistamines and drug interactions 121

Interactions with grapefruit juice small but statistically significant increase in the QTc inter-
val (from 420 6 14 msec with water to 434 6 15 msec with
The discovery that the metabolism of felodipine was
grapefruit juice), whereas grapefruit juice given 2 h after
inhibited by grapefruit juice but not by orange juice [56]
terfenadine produced no change (408 6 18 vs. 407 6
focused attention on the possible active constituent(s)
22 msec). The difference between simultaneous and
responsible for CYP3A inhibition. Based on the known
delayed grapefruit juice is consistent with the data for
inhibitory activity of bioflavonoids on P450 oxidations
other substrates. The inhibitory effect of grapefruit juice is
in vitro [57] and differences in composition between grape-
primarily during the absorption/first pass metabolism phase;
fruit and oranges it was believed that the active agent was
grapefruit juice does not affect the clearance of systemic
naringenin and its precursor naringin. However, the in vitro
doses of other CYP3A substrates such as cyclosporin [69] or
activity of flavonoids was not reproduced by in vivo inter-
nifedipine [70]. It is probable that much of the first-pass
action studies using oral dosage of either naringin [58] or a
metabolism of CYP3A4 substrates such as terfenadine,
very high dose of quercetin [59]. In addition, the in vitro
cyclosporin and nifedipine occurs at the level of the
inhibitory activity of grapefruit juice exceeds that of an
intestinal wall.
equivalent concentration of naringin and there was not
The magnitude of the change in the pharmacokinetics of
conversion of naringin to naringenin under the in vitro
terfenadine produced by grapefruit juice was defined [5]
conditions used [60]. Recently, attention has focused on
using a sensitive radioimmunoassay method with a limit of
furanocoumarins (such as 60 ,70 -dihydroxybergamottin [61];
detection of 0.1 ng/ml. Grapefruit juice, given 30 min before
and dimers [62]) which are potent inhibitors of CYP3A4
a single oral dose of terfenadine (120 mg) produced a 3.5-
[62]; these compounds also cause a rapid loss of CYP3A4
fold increase in the maximum concentration of terfenadine
activity from a cell line in vitro [61], consistent with the loss
per se and a 2.5-fold increase in the AUC. This was
in enzyme activity reported in vivo. 60 ,70 -Dihydroxyberga-
accompanied by a small and non-significant increase in
mottin did not decrease CYP1A2 or CYP2D6 [61]; grape-
the change in QTc interval detected at the peak plasma
fruit juice produces a weak inhibition of the metabolism of
concentration.
CYP1A2 substrates in vivo [63, 64], although some studies
reported no activity in vivo [65, 66]. 60 ,70 -Dihydroxyberga-
mottin is present in grapefruit juice but not in orange juice Other in vivo interaction studies
[67], an observation consistent with the original clinical
Co-administration of clinically relevant doses of zileuton (a
observations with felodipine.
5-lipoxygenase inhibitor) with terfenadine resulted in a
Many studies on drug–grapefruit juice interactions have
small but measurable and significant increase in the maxi-
used double-strength grapefruit juice; recent studies with
mum plasma concentration and AUC of terfenadine (by
terfenadine have shown significant effects with regular-
35%) in healthy volunteers, but this was not associated with
strength grapefruit juice [68] and freshly squeezed juice [5].
significant ECG changes [71] indicating that this interaction
was not likely to be of clinical importance.
The antidepressant nefazodone increases the AUC of
Terfenadine
CYP3A substrates, such as triazolam, and coadministration
Coadministration of terfenadine (60 mg twice daily) for of nefazodone with terfenadine or astemizole is contra-
7 days and grapefruit juice gave measurable plasma con- indicated [72]. Fluvoxamine, fluoxetine and sertraline
centrations of terfenadine in 6/6 subjects when taken simul- inhibit both CYP3A4 and CYP2C [73] and these may also
taneously, but in only 2/6 subjects when the grapefruit juice show interactions with terfenadine and astemizole (but see
was taken 2 h after the terfenadine, and 0/6 subjects when below).
the same dosage of terfenadine was taken in the absence of
grapefruit juice [4]. The maximum detected plasma con-
In vitro interaction studies
centrations of terfenadine with grapefruit juice were 5–
11 ng/ml, but the sensitivity of the assay method precluded In vitro studies using primary cultures of human hepato-
characterization of the pharmacokinetic profile. Grapefruit cytes, have confirmed the metabolic basis for many of the in
juice also produced a statistically significant increase in the vivo interactions with terfenadine. The C-oxidation was
AUC of the acid metabolite when given simultaneously inhibited by ketoconazole > itraconazole > cyclosporin >
(þ55%) and when given 2 h after terfenadine (þ22%); the erythromycin > naringenin (a grapefruit constituent) [74]
interindividual variability in the data in groups with and and N-dealkylation was also inhibited but with a slightly
without grapefruit juice raises doubts about the clinical different order of potency. These in vitro rankings should be
significance of this difference. Interestingly, simultaneous interpreted with caution because in vivo activity will depend
administration of grapefruit juice and terfenadine caused a on the dosage and kinetics of the inhibitors. For example,
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122 A. G. Renwick
selective serotonin re-uptake inhibitors (SSRIs) were weak
in vitro inhibitors of terfenadine oxidation by human micro-
somes [75] but in vitro–in vivo scaling indicated that this
would not be of clinical significance at normal clinical doses
[76], in contrast to ketoconazole and itraconazole which
were 20 times more potent in vitro and have been shown to
have significant effects in vivo. Interestingly ketoconazole,
fluconazole, itraconazole, erythromycin, clarithromycin and
troleandomycin were potent inhibitors of human micro-
somal terfenadine metabolism (IC50 values of < 10 nM) but
weak inhibitors of rat microsomes (IC50 values of > 80 nM)
[77] and of oxidation of terfenadine by rat hepatocytes [78].
In vitro studies have also shown the potential for other
interactions with CYP3A substrates such as ritonavir [79]
and saquinavir [80] but their in vivo significance has not
been defined.
Conclusions
The potential for clinically important interactions with non-
sedating antihistamines can be subdivided on the basis of
the metabolic fate and biological activity of the parent drug
and metabolite.
Astemizole and terfenadine are both substrates for
CYP3A4 and have been associated with clinical cases of
torsade de pointes. The relationship between drug inter-
actions and cardiovascular risk is clear in the case of
terfenadine, because the active antihistamine metabolite
(fexofenadine) does not produce cardiac effects and
coadministration of inhibitors of CYP3A4 was part of the
clinical scenario in the cases of torsade de pointes. The
situation with astemizole is probably similar but less clearly
defined as the antihistamine metabolite has been reported to
show cardiac effects; the long half-lives of the parent drug
and especially the metabolite, mean that short-term inter-
action studies are inadequate to define the potential for
effects on the QT interval. Ebastine is oxidized to the active
antihistamine metabolite carebastine and it is probably
similar to terfenadine in its activities, metabolism and
potential for clinically important interactions.
The published data do not allow a definitive conclusion
on the potential for clinically significant interactions with
azelastine. Of the non-sedating antihistamines it appears
that fexofenadine, cetirizine and loratadine are the least
likely to undergo a clinically significant drug interaction
[81]. Cetirizine and fexofenadine undergo limited meta-
bolism and are not associated with cardiac effects. In
contrast, loratadine undergoes extensive oxidation largely
by CYP3A, and would show pharmacokinetic interactions
with azoles and macrolide antibiotics; however, neither
loratadine or the main metabolite affect cardiac Kþ
channels at therapeutic concentrations, and therefore these
interactions would not represent a safety concern.
q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, Supplement 3, 116–124
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