Biochemical Pharmacology 66 (2003) 1123–1126
`Commentary
`
`Compared pharmacological characteristics in humans of racemic
`cetirizine and levocetirizine, two histamine
`H1-receptor antagonists
`
`Jean-Paul Tillementa,*, Bernard Testab, Franc¸oise Bre´ea
`aLaboratoire de Pharmacologie, Faculte´ de Me´decine de Paris XII, F-94010 Creteil, France
`bInstitut de Chimie The´rapeutique, Ecole de Pharmacie, Universite´ de Lausanne, CH-1015 Lausanne, Switzerland
`
`This article is dedicated to the memory of Dr. Joachim Mayer (1949–2001), colleague and friend
`
`Abstract
`
`1
`The potent histamine H1-receptor antagonist cetirizine (Zyrtec
`) is a racemic mixture of levocetirizine (now available under the
`1
`) and dextrocetirizine. In this Commentary, we examine some biological properties of cetirizine and levocetirizine,
`trademark Xyzal
`namely enantioselectivity in pharmacological activity and pharmacokinetic properties, with emphasis on the possibility of racemization,
`the compared behavior of the two enantiomers, and the potential for interactions with other drugs. Recent data demonstrate that the
`antihistaminergic activity of the racemate is primarily due to levocetirizine. Levocetirizine is rapidly and extensively absorbed, poorly
`metabolized, and not subject to racemization. Its pharmacokinetic characteristics are comparable after administration alone or in the
`
`1 vs. 0.60 L kg1). Moreover, the non-
`racemate. Its apparent volume of distribution is smaller than that of dextrocetirizine (0.41 L kg
`1 vs.
`renal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 mL min
`1). Our conclusion is that levocetirizine is indeed the eutomer of cetirizine. The evidence reviewed here confirms
`29.2 mL min
`preclinical findings and offers a rationale for the chiral switch from the racemate to levocetirizine.
`# 2003 Elsevier Inc. All rights reserved.
`
`Keywords: Chiral switch; Cetirizine; Levocetirizine; Eutomer; Distomer; Racemate; Racemization; Volume of distribution; Drug–drug interactions
`
`1. Introduction
`
`1
`) is a second-generation antihista-
`Cetirizine (Zyrtec
`mine indicated for the treatment of seasonal allergic rhi-
`nitis, perennial allergic rhinitis and chronic idiopathic
`urticaria, in adults and children of 6 or more years. Its
`principal pharmacological effects are mediated through
`selective inhibition of peripheral histamine H1-receptors,
`and its pharmacokinetic properties explain its good toler-
`ability in patients. Indeed, the use of cetirizine is associated
`with a low incidence of anticholinergic effects such as dry
`mouth. Furthermore, it causes little sedation and has no
`cardiac adverse effects unlike highly lipophilic antihista-
`mines [1]. Moreover, it can be safely administered with
`virtually any other drug, as it does not affect their rate of
`
`* Corresponding author. Tel.: þ33-1-49-81-36-61;
`fax: þ33-1-49-81-35-94.
`E-mail address: tillement@univ-paris12.fr (J.-P. Tillement).
`
`0006-2952/$ – see front matter # 2003 Elsevier Inc. All rights reserved.
`doi:10.1016/S0006-2952(03)00558-6
`
`metabolism. This is due to the fact that it has neither
`inducing nor inhibiting effects on the major drug-metabo-
`lizing enzymes [2].
`Cetirizine is a racemate which consists in equal amounts
`of (R)-levocetirizine and (S)-dextrocetirizine (Fig. 1).
`In most medicinal racemates, one of the enantiomers is
`more active than the other [3], and a number of studies
`have shown that cetirizine and its enantiomers follow this
`rule.
`As usual with racemates, it is useful to examine whether
`there is a scientific justification for a chiral switch to the
`eutomer. This can be done using the decision tree proposed
`by one of us [4], which consists in comparing the degree of
`enantioselectivity of the two enantiomers in pharmacody-
`namic and pharmacokinetic properties, in checking for
`interactions between enantiomers and with other drugs,
`and in assessing the absence of interconversion between
`enantiomers (racemization) [5]. This Commentary covers
`significant studies published on these aspects.
`
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`1124
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`J.-P. Tillement et al. / Biochemical Pharmacology 66 (2003) 1123–1126
`
`Cl
`
`Cl
`
`H
`
`N
`
`N
`
`COOH
`
`H
`
`N
`
`N
`
`COOH
`
`O
`
`O
`
`(R)-levocetirizine
`
` (the eutomer)
`
`(S)-dextrocetirizine
`
`
`
` (the distomer)
`
`Fig. 1. The chemical structure of (R)-levocetirizine and (S)-dextrocetirizine.
`
`2. Is enantioselectivity observed in the
`pharmacological activity of cetirizine?
`
`In binding assays, levocetirizine has demonstrated a
`2-fold higher affinity for the human H1-receptor compared
`to cetirizine, and an approximately 30-fold higher affinity
`than dextrocetirizine [6]. The difference in affinities
`between the two enantiomers is mostly accounted for by
`their different dissociation rates from the H1-receptor, with
`levocetirizine demonstrating a far longer dissociation half-
`life than dextrocetirizine (Table 1).
`In healthy subjects, levocetirizine inhibited histamine-
`induced wheal and flare responses to the same extent as
`cetirizine, with a maximum effect at 6 hr post-dose and a
`duration of action greater than 24 hr. In contrast, dextro-
`cetirizine was less effective at the same dose [7]. Notably,
`at 32 hr post-dose the histamine-induced wheal response to
`levocetirizine was statistically superior to that to cetirizine
`[7]. Levocetirizine (5 mg) and cetirizine (10 mg) also
`inhibited histamine-induced increases in nasal airway
`resistance while dextrocetirizine failed to demonstrate
`any significant antihistaminergic activity [8]. Thus, the
`H1-antagonist activity of cetirizine is primarily due to
`levocetirizine, which is considered to be the most active
`enantiomer (i.e. the eutomer), while dextrocetirizine is the
`least active enantiomer (the distomer).
`This can be a first argument to remove the distomer from
`the racemate and develop the eutomer. However, it is clear
`that such a decision cannot be based on this single criterion.
`
`Table 1
`Binding characteristics of levocetirizine and dextrocetirizine to human H1-
`receptors expressed in Chinese hamster ovary (CHO) cells [6]
`
`(mM1 min1)a
`
`k1
`kþ1
`t1/2
`1)b(min
`1)c(min
`
`
`
`
`0.005  0.002 142
`2.3  0.4
`Levocetirizine
`0.12  0.05
`Dextrocetirizine 1.6  0.7
`6
`a Association kinetic constant  SD.
`b Dissociation kinetic constant  SD.
`c Dissociation half-life.
`d SD.
`
`d
`
`pKi
`
`8.5  0.1
`7.1  0.1
`
`The possibility of adverse reactions caused by the eutomer
`but not seen with the racemate is a major criterion of
`decision. It is therefore important to underline here that no
`serious adverse event was seen in the two clinical studies of
`levocetirizine discussed below [9,10].
`Besides these pharmacodynamic considerations, phar-
`macokinetic criteria must also be taken into account, e.g.
`the possibility of racemization of the eutomer, the com-
`pared pharmacokinetics of the two enantiomers, and a
`possible influence of the distomer on the in vivo behavior
`of the eutomer.
`
`3. Is an interconversion between enantiomers
`(racemization) likely to occur?
`
`Following the oral administration of [14C]levocetirizine
`dihydrochloride (5 mg) to four subjects, the pharmacoki-
`netic parameters of total radioactivity and levocetirizine
`were monitored separately [10]. No difference was seen
`between the respective Cmax, tmax and AUC values, and
`there was no appearance of dextrocetirizine in human
`plasma or urine samples following levocetirizine dosing
`[10]. This is a clear indication that levocetirizine does not
`racemize in the body, a configurational stability further
`confirmed when levocetirizine and dextrocetirizine were
`incubated separately in human plasma.
`Similarly, incubation of cetirizine enantiomers in buffer
`solutions of pH 7.4 at room temperature did not reveal the
`slightest occurrence of racemization even after days [11].
`Thus, there is overwhelming evidence for the great con-
`figurational stability of levocetirizine.
`
`4. Is enantioselectivity observed in the
`pharmacokinetic properties of cetirizine?
`
`The intestinal absorption of H1-antagonists is usually
`complete [1,10], and cetirizine and levocetirizine are no
`exception to this rule. Indeed, with its Cmax reached within
`1 hr, levocetirizine shows the same rapid and extensive
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`
`1125
`
`intestinal absorption as cetirizine [12,13]. This is reflected
`in a total recovery of 98.3% of the dose as determined in
`the radiolabel study, and a higher value than that the 95%
`previously measured for cetirizine [14]. Cetirizine, and
`hence its enantiomers, exist almost exclusively as a zwit-
`terion in the pH region 3.5–7.5 [15]. Due to conformational
`flexibility and the formation of an internal ionic bond, the
`positive and the negative charge partly neutralize each
`other, rendering the molecule more lipophilic and hence
`better available for passive absorption.
`Although the pharmacokinetics of levocetirizine and
`cetirizine are similar,
`some differences have been
`observed. The apparent volume of distribution of levoce-
`tirizine is significantly lower than that of dextrocetirizine
`(Table 2). A low volume of distribution is a valuable
`property for H1-antagonists, both in terms of safety and
`efficacy [16], since it implies a lack of exposure of organs
`which are not therapeutic targets but where toxic reactions
`may be elicited. Furthermore, a low volume of distribution
`reduces the risk of dose-dependent toxicity, individual
`variations in therapeutic effect, and the potential for
`drug–drug interactions [1]. The fact that the plasma protein
`binding of levocetirizine (91.2%) [17] is slightly higher
`than that of cetirizine (88–90%) may explain the lower
`distribution volume of the former [18].
`
`5. How extensively are cetirizine enantiomers
`metabolized?
`
`The non-renal clearance of levocetirizine was found to
`be significantly lower
`than that of dextrocetirizine
`(Table 2). The non-renal clearance (i.e. total minus renal
`1 for levocetirizine
`clearance, i.e. 11.8 and 29.2 mL min
`and dextrocetirizine, respectively) corresponds in fact to
`the hepatic clearance. Such a difference suggests that more
`dextrocetirizine than levocetirizine is metabolized in the
`
`liver, although biotransformation is low in both cases and
`probably of no clinical relevance. Indeed, metabolic profil-
`ing and quantification have demonstrated that like the
`racemate, levocetirizine is poorly metabolized [19]. A very
`low level of biotransformation was also confirmed by the
`equivalence of pharmacokinetic parameters seen when
`comparing total radioactivity and unchanged levocetirizine
`in plasma [10].
`This is an important finding since it implies that meta-
`bolic interactions with extensively transformed drugs
`are unlikely for dextrocetirizine and even more so for
`levocetirizine. In contrast, many other second-generation
`antihistamines of high lipophilicity are extensively meta-
`bolized by hepatic and intestinal cytochromes P450, par-
`ticularly CYP2D6 and CYP3A4 [14]; the concomitant use
`of antifungals, macrolides or cimetidine, to cite a few, can
`dramatically inhibit these enzymes, causing accumulation
`of unchanged antihistamine and the possible occurrence of
`overdosage.
`
`6. Are the enantiomers of cetirizine involved in
`mutual pharmacokinetic interactions?
`
`A recent investigation has answered this question [9]. A
`two-way randomized, cross-over design was employed
`with a washout period of 7 days between two treatments,
`involving either levocetirizine dihydrochloride (10 mg) or
`cetirizine dihydrochloride (20 mg) dissolved in 50 mL of
`uncarbonated water, administered to 24 healthy subjects
`(12 males, 12 females). The plasma and urinary pharma-
`cokinetic parameters of levocetirizine administered alone
`or in the racemate were compared. The results (Table 2)
`show clearly that the behavior of levocetirizine was not
`influenced by the presence of its enantiomer. Compared
`with the latter, levocetirizine had a higher plasma AUC, a
`higher Cmax, a longer terminal half-life (t1/2) and a smaller
`
`Table 2
`Plasma and urinary pharmacokinetic parameters of levocetirizine and dextrocetirizine following a single dose of levocetirizine or cetirizine [9]
`
`Drug administered
`
`Levocetirizine dihydrochloride (10 mg)
`
`Cetirizine dihydrochloride (20 mg)
`
`Levocetirizine
`Drug monitored
`4.14  0.74
`1)  SD
`1 hr
`AUC (mg mL
`0.51  0.11
`1)  SD
`Cmax (mg mL
`0.73  0.33
`tmax (hr)  SD
`7.76  1.59
`1)  SDa
`t1/2 (hr
`41.6  7.7
`1)  SDb
`Cl/F (mL min
`0.41  0.10
`1)  SDc
`Vz/F (L kg
`6810  1023
`Ae (mg)  SDd
`68.1  10.2
`Fe (%)  SDe
`29.8  7.7
`1)  SDf
`CLR (mL min
`a Terminal half-life calculated as ln2/lz, where lz is the apparent first-order terminal rate constant.
`b Apparent total body clearance (calculated by dividing the dose administered by the AUC), divided by the bioavailability (F).
`c Apparent volume of distribution, divided by the bioavailability (F).
`d Total amount excreted over the entire urine sample collection.
`e Relative cumulative urinary excretion.
`f Renal clearance calculated as Ae/AUC(0–48 hr).
`
`Levocetirizine
`4.09  0.65
`0.51  0.10
`0.80  0.29
`7.80  1.96
`41.7  6.3
`0.42  0.11
`7260  1285
`72.6  12.8
`32.0  8.3
`
`Dextrocetirizine
`1.91  0.39
`0.29  0.06
`0.82  0.33
`5.52  1.85
`90.60  17.16
`0.60  0.14
`6360  1330
`63.6  13.3
`61.4  17.7
`
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`
`Stereoselectivity in receptor recognition
`
`References
`
`In vivo efficacy
`
`Limited
`No racemization biotransformatio
`
`n
`
`No pharmacodynamic or pharmacokinetic
`interaction between enantiomers
`
`Absence of adverse effects caused by
`the eutomer but not by the racemate
`
`Rationale for the selection of the eutomer
`
`Fig. 2. A sequence of scientific criteria to be applied when choosing
`between a racemate (this work, cetirizine) and its eutomer (this work,
`levocetirizine) (simplified from [4]).
`
`volume of distribution (Vd). These results lead to the
`conclusion that the pharmacokinetic parameters of levo-
`cetirizine are not influenced by dextrocetirizine, being
`neither increased nor decreased.
`
`7. Conclusion: the racemate or the eutomer?
`
`The decision to develop a eutomer rather than a racemate,
`or to carry through a chiral switch, is based on scientific and
`commercial criteria. Scientific criteria, the only one of
`concern to us, can be organized in a decision tree [4], a
`simplified version of which is shown in Fig. 2.
`it
`Applying these successive criteria to cetirizine,
`appears indeed that levocetirizine is the eutomer for phar-
`macodynamic and pharmacokinetic reasons. To summarize,
`all evidence available indicates that
`levocetirizine is
`intrinsically more active and more efficacious than dextro-
`cetirizine, and for a longer duration. Furthermore, its phar-
`macokinetic behavior appears more favorable due to a lower
`volume of distribution and a slower renal clearance. Con-
`sidering the pharmacokinetic–pharmacodynamic model of
`inhibition of histamine-induced skin reactions by cetirizine
`[18], the plasma levels achieved by a dose of 5–10 mg of the
`eutomer are sufficient to reach maximal antihistaminergic
`effects.
`In our view, these findings offer a first rationale for the
`therapeutic use of the eutomer administered alone.
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