Acta Tropica 86 (2003) 141 /159

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Review article

Albendazole, mebendazole and praziquantel. Review of

non-clinical toxicity and pharmacokinetics
A.D. Dayan *,1
Parasitic Diseases and Vector Control (PVC), Communicable Diseases Control, Prevention and Eradication (CPE), World Health
Organization, CH-1211 Geneva 27, Switzerland

Abstract
The pharmacokinetics and toxicity of albendazole, mebendazole and praziquantel are extensively reviewed, drawing
on original published work and reviews in the open scientific literature and on assessments by international agencies
and official regulatory bodies in Europe and the USA. Information about human and veterinary medical uses and
adverse reactions is evaluated. The totality of the non-clinical information available about these long-established drugs
may not comply with current official guidelines for new medicines but reasons are given why the deficiencies are only
apparent and the data gaps can be replaced by other results, largely obtained from the target species and the many years
of clinical experience of safe use of these drugs in humans and animals.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Albendazole; Mebendazole; Praziquantel; Toxicity; Pharmacokinetics; Risk assessment

1. Introduction
The reviews have been prepared for WHO
Tropical Diseases Research (TDR) as part of the
documentation to support an Informal Consultation in Geneva, in April 2002, on Use of
Praziquantel during Pregnancy and Lactation

* Tel.:
/41-22-791-3824; fax:
/41-22-791-4869.

E-mail address: engelsd@who.ch (A.D. Dayan).
1
Formerly of Faculty of Medicine, Queen Mary and
Westfield College, University of London, UK.

and Albendazole/Mebendazole in Children under

24 Months.
They cover information on published papers on
the results of preclinical toxicity testing and
pharmacokinetic and drug metabolism studies of
all three drugs identified by searching the computerised databases Medline, Toxline, Embase and
SIGLE, from 1996 to the end of 2001, plus
consultation of major monographs and textbooks.
The drugs have been reviewed and accepted for
various clinical uses by a number of major
national and international agencies concerned
with human and veterinary medicines and their

0001-706X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0001-706X(03)00031-7

142

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

published evaluations have also been used. In

addition, Drs M. Hanisch, Bayer, J. Horton,
GSK, K. Troester, E. Merck and P. Vanparys,
Johnson and Johnson, have generously provided
additional information from company records.
Valuable advice and professional views about
veterinary understanding and experience of these
drugs has generously been made available by
Professor Q. McKeller, Scottish Agricultural Research Institute. Mr A. Gray, UK Veterinary
Medicines Directorate, has kindly sent information from the publicly available Suspected Adverse Reactions Scheme for veterinary medicines
in the UK. The advice from Professor McKellar
and Mr Gray has been provided in a personal
capacity and does not represent official views of
the organisations where they work.
For each drug, after a summary of the available
information, there is a brief section presenting a
personal assessment of the data and suggestions
about the types of non-clinical information that
might be provided nowadays if the drugs were
newly developed and were just being presented for
registration for the first time as medicines for use
by humans. It is not suggested that new or
additional animal experiments are necessary for
the assessment of safety, because of the extent of
our clinical experience of them in humans and
farm and companion animals. The topics not
covered by experimental data should serve instead
to focus attention on aspects deserving particular
clinical attention.
It is a common experience on making a retrospective evaluation of old drugs, i.e. those
invented and developed several decades previously, that the experimental, non-clinical data
about activity, toxicity, kinetics etc would be
considered inadequate on strict application of
todays professional and regulatory expectations.
However, for such drugs, which will have undergone rigorous evaluation by standards considered
appropriate at the time they were first introduced,
there will be much clinical experience of their use
in human and animal patients. That vital experience in the target species will almost always
supersede any need for additional animal or other
laboratory experiments. Similarly, experiments
and tests done prior to the introduction of the

GLP regulations are often entirely valid and

acceptable.
In the instance of the present drugs, this is
shown by the published evaluations of official
national and international regulatory bodies,
which have made expert assessments of available
information and have provided critical judgements
about the acceptability of the data in the official
licensing and registration of the three products for
therapeutic medical use. The official prescribing
advice (Datasheet or Patient Information sheet)
will reflect both evaluation of the quality and
adequacy of the non-clinical data and the complementary findings about clinical safety and
adverse actions in various exposed groups, judged
according to the current criteria and risk-benefit
considerations of that agency. It is important that
Prescribing Instructions are legally binding statements agreed between individual national regulatory authorities for human and veterinary
medicines, based on national assessment of available information about safety and efficacy and
balanced against the risks of the appropriate
disease as perceived by that Agency in the light
of national circumstances. There is no place in
drug development and usage for complacency or
multiple standards but it must be realised that
regulatory approval and the corresponding Prescribing Information are specific to each country
and reflect national circumstances and perceptions. The balance of risk and benefit will often
differ between countries and so, sometimes, will
assessment of the information.
The assessment of preclinical and other information that goes into evaluation of the safety of
residues of a medicine given to food animals,
which commonly involves both international agencies, such as JECFA and JMPR, as well as
national or supranational authorities, for example
the US FDA and European Medicines Evaluation
Agency, is directed at determining what level of
residues in the human diet may be considered
safe according to very conservative criteria. It is
focused, therefore, on the ultimate consumer
rather than the individual patient, and is intended
to ensure safe consumption over a lifetime and not
treatment of the individual disease. These differences in purpose understandably lead to quantita-

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

143

tive differences in recommended safe levels of

each drug in question.
All these points should be considered when
reading the summaries of preclinical data and the
differences which may sometimes occur between
nationally approved advice about the circumstances when a drug may be used, the doses and
duration of treatment, anticipated adverse actions
and the classes of patient for whom use is or is not
approved.
The personal comments, in which apparent
deficiencies of data have been noted, reflect my
own view of what non-clinical test results might
now be expected in a brand new registration
dossier. They must be compared with the extent
and adequacy of other findings about each drug,
especially clinical experience over many years,
when considering the final recommendations of
the Consultation.

2. Albendazole
CAS 54965-21-8
Albendazole (ALB) is a typical, broad spectrum
benzimidazole antiparasitic agent, first approved
for human use in 1982.
Dosage. In Britain (Martindale, 1993a; ABPI,
1999a,b) the recommended dosage schedule for
echinococcosis is:
Patients

/60 kg 400 mg b.d. for 28 days. Can

repeat every 14 days for three cycles.
Has been given continuously for 20
months.
B/60 kg appropriate dosage adjustment
is not possible with the available 400
mg tablet.
Children: limited experience; no dosage recommendation. Use in childrenB/6 years
old is not recommended
It should not be administered during pregnancy or in women thought to be pregnant.
Women of child bearing age should be advised to
take effective precautions. . .against conception
during and within one month after completion of
treatment. . . (ABPI, 1999a,b).

Fig. 1. Albendazole, albendazole sulphoxide and albendazole

sulphone.

Veterinary Use. Approved in Britain for use in

cattle and sheep, including pregnant animals and
the young (NOAH, 2001).
ALB is (5-(propylthio)-1H-benzimidazol-2yl)carbamic acid methyl ester. Its structure and
those of its principal metabolites are shown in
Figs. 1 and 2.
ALB has vermicidal, ovicidal and larvicidal
activity by binding to intracellular tubulin, preferentially affecting parasites, and inhibiting essential absorptive functions in the organisms
(summarised in EMEA, 1997; Dollery, 1999a).

2.1. Pharmacokinetics and metabolism

No single comprehensive survey of the PK and
metabolism of ALB in animals was found for
comparison with information from humans but
there were extensive, scattered results from many

144

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

Fig. 2. Metabolism of albendazole [after Penicaut et al., 1983].

experiments and evaluations by several regulatory

agencies.
Several analytical techniques suitable for blood
and plasma (and hydatid cyst fluid) from animals
and humans have been described, most based on
liquid/liquid extraction followed by HPLC with
UV detection (Zeugin et al., 1990).
2.1.1. Absorption, distribution and excretion
ALB is relatively insoluble in water and most
organic solvents, properties that influence its
absorption and behaviour in the body.
In the mouse and rat oral absorption of ALB is
about 20 /30% and in cattle it is about 50%,
compared to about 1/ B/5% in humans (JECFA,
1989a; EMEA, 1997; ABPI, 1999a; Dollery, 1999a;
PDR, 2001a). As it undergoes very rapid first pass
metabolism in all species, the unchanged drug has

not been reliably detected in plasma (JECFA,

1989a,b; EMEA, 1997; Dollery, 1999a). Plasma
levels of the initial oxidised metabolites (the
sulphoxide and sulphone) in all species are much
higher than of the parent drug. The sulphoxide is
generally considered to be the active metabolite
responsible for the therapeutic activity of ALB.
Absorption in animals and man is fast, the peak
level of radioactivity after oral administration of
14
C-ALB and of the intact drug (as sulphoxide)
being reached within 2/3 h in man, the rat and
sheep (JECFA, 1989b; Dollery, 1999a).
A fatty meal or eating enhances absorption up
to 5-fold in humans and animals (Dollery, 1999a;
Sanchez et al., 2000a,b; PDR, 2001a) and so in the
rat did perfusion of the stomach ex vivo with 5%
ethanol in the rat (Justel et al., 1994). The increase
in both instances has been attributed to greater

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

dissolution of the water insoluble drug in the lipid

matrix, food or ethanol. Fasting has been shown
to increase absorption and to prolong the mean
plasma residence time in calves (Sanchez et al.,
2000b).
The relationship between the administered oral
dose and the plasma level or AUC of parent drug
or oxidised metabolites has not been directly
reported, but the PDR (2001a,b) states that it is
dose-proportional (after a fatty meal). An oral
dose of 400 mg (say about 6/8 mg/kg in an adult)
as a tablet or suspension led to a cmax in man of
ALB sulphoxide 0.16 mg/L, in the rat ALB 10 mg/
kg PO gave a cmax of the sulphoxide in plasma of
6.6 mg/L, 30 mg/kg in the rabbit resulted in a cmax
of 8.8 mg/L and the dose of 10 m/kg in cattle and
sheep led to a cmax of the sulphoxide of 0.6 and 2.5
mg/L respectively. (Authors Note: The report
states mg/L but this is likely to be a misprint
for mg/L). Dollery (1999a) reports a cmax of the
sulphoxide in plasma of 0.22 /0.25 mg/L 2 /3 h
after an oral dose in man of ALB 400 mg (say
about 6 /8 mg/kg) and the PDR reports a cmax of
0.46 /1.58 mg/l (average 1.31 mg/l) after the same
dose.
ALB sulphoxide is widely distributed throughout the body; it is 70% bound to plasma proteins
(PDR, 2001a).
Clearance of the parent drug is very rapid in all
species (PDR, 2001a) but that of the sulphoxide
and sulphone metabolites is slower; in man, rat
and sheep t1/2el ALB */not reported (plasma level
below LoQ of 10 /20 mg/l in most instances); the
t1/2el of ALB sulphoxide is 8 /12 h in man and
probably close to 4 h in the rat (latter estimated
from Delatour et al., 1984). After an oral dose of
ALB 10.6 mg/kg in the rat, the metabolites were
almost undetectable in plasma by 18/24 h; in the
sheep there was complete clearance of drug from
the blood and body by 96 h (JECFA, 1989b).
Excretion occurs very largely as metabolites in
bile. Only metabolites of ALB are excreted
in animals and man, as metabolism is very
extensive.
2.1.2. Metabolism
Metabolism is particularly important, because
ALB sulphoxide is the therapeutically active form

145

of the drug (Gotschall et al., 1990). It is produced

by extensive first pass metabolism in the liver and
probably the intestinal wall in animals and man
(Fig. 2; Dollery, 1999a; PDR, 2001a); further
oxidation results in the sulphone. Independent
oxidative pathways affect the alkyl side chain
and the aromatic ring. The carbamate group is
rapidly removed by hydrolysis, too (Gyurik et al.,
1981; Penicaut et al., 1983; EMEA, 1997; Dollery,
1999a,b,c; PDR, 2001a). Metabolism is similar in
man, the rat, dog and other animals (Gyurik et al.,
1981; EMEA, 1997; JECFA, 1989b).
Metabolism depends both on cytochrome P450
oxidases and other flavin-containing oxidases
(Fargetton et al., 1986; Amri et al., 1987; Gotschall
et al., 1990).
Repeated administration of ALB does alter its
own kinetics, probably by affecting its metabolic
clearance by inducing at least the P450s
involved in its own metabolism (Gotschall et al.,
1990).
ALB sulphoxide has a chiral centre and it
appears that formation of ALB (/) sulphoxide
depends on P450 enzymes, whereas that of ALB
(
/) sulphoxide depends on flavin enzymes in all
species examined (Delatour et al., 1991a,b; Moroni
et al., 1995). Subsequent oxidation to ALB sulphone is dependent on P450 isozymes (Amri et al.,
1988). In man ALB (
/) sulphoxide is the predominant form in plasma (Delatour et al.,
1991a,b), the relative AUCsss being 8/9 for the
(
/)/(/)sulphoxide and sulphone (Marques et al.,
1999). In sheep, males had /30% higher AUCsss
of the (
/) than the (/) enantiomers (Capece et
al., 2000).
P450 1A1 is involved in the metabolism of ALB
(PDR, 2001a); it has not been proven that other
isozymes are also involved, but the inhibitory
action of cimetidine (PDR, 2001a) suggests that
3A4 may also play a role. Co-administration of
cimetidine and praziquantel (Homeida et al., 1994;
PDR, 2001a) affects the kinetics of ALB, and leads
to a moderate fall in the plasma ALB sulphoxide
level, probably by induction of the second, sulphonation step (Souhaili-El Amri et al., 1988a,b).
It is not certain whether there is also some change
in absorption but the effect is more likely to be due

146

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

to an action on the P450 isozymes involved in the

metabolism of ALB.
The importance of CYP 3A4 in man has been
indicated by other in vitro experiments (Rawden et
al., 2000).
ALB sulphoxide exists as two enantiomers */the
(
/) and (/) forms. Man and the dog differ from
the rat in that the (
/) form is found in a much
higher proportion in plasma than in the rat, in
which the (/) form is predominant (Delatour et
al., 1991a). The differences can be as much as
(ratios of AUCs after same dose):
Man
(/) 20:(
/) 80
Dog
30:70
Rat
59:41
(Delatour et al., 1991a)
There are reasons for considering that formation of the (
/) enantiomer is due to oxidation by a
flavine-adenine-dinucleotide mono-oygenase and
that of the (/) occurs via P450 enzyme. Differences in the amount or activity of these enzymes
may be the source of the species differences in
kinetics of the enantiomers.
There are toxicological data, including reproduction test results from various animal species,
backed by further studies in which the (
/)
enantiomer was the predominant enantiomer in
the bovine, ovine and caprine (Delatour et al.,
1991b) and in which teratogenicity and clinical
developmental abnormalities have not been reported after conventional therapeutic usage. Thus,
it may be argued that there has been appropriate
(albeit unconventional) toxicological investigation
of both the enantiomers.
2.1.3. Authors comments
ALB is drug that has long been registered as a
pharmaceutical in many major countries and it has
also been exhaustively evaluated for use in food
producing animals by JECFA.
Although all the data are not available in the
public domain to compile a simple table comparing pharmacokinetic parameters in man and
laboratory and food animals, it is apparent that
its kinetics and metabolism are qualitatively similar in all species and that there are probably no
major deficiencies in the pharmacokinetic and

metabolic data on which JECFA and the EMEA

have based their published assessments. It is
important that both international agencies felt
able to derive ADIs for man and so to indicate
that the overall data were satisfactory both in
extent and quality (JECFA, 1989a,b; EMEA,
1997). Similarly, major regulatory agencies for
drugs for man have not required extensive precautions or warnings about areas of ignorance concerning pharmacokinetics and metabolism in
humans or derived from preclinical dossiers
(ABPI, 1999a; PDR, 2001a).
In the context of the present discussion there
does not appear to be publicly available information about kinetics in babies, in pregnancy or
about excretion of the drug and its metabolites in
milk. There has been investigation of kinetics in
young children (Okelo et al., 1993).

3. Toxicity testing
3.1. Acute toxicity
As reported in JECFA
(1989b), the oral LD50 was
mouse

/3000 mg/kg
rat
1320 /2400 mg/kg
rabbit
500 /1250 mg/kg
Signs at autopsy were non-specific apart from
some intestinal haemorrhage in the rat and fluid in
the rabbit.
3.2. Repeated dose toxicity testing
In comprehensive oral studies in the mouse rat,
dog, ALB in doses larger than about 30 /40 mg/kg/
day for 4/90 days caused some retardation of
weight gain, readily reversible anaemia and slight
leucopenia, hypercholesterolaemia and other, nonspecific and variable changes in clinical chemistry
test results and slight proteinuria in the rat.
Autopsy and histopathological examination revealed relative enlargement of the liver in the rat
and dog given
/40 /60 mg/kg/day with some
enlargement of centrilobular hepatocytes, and
testicular hypoplasia in mice receiving 400 mg/
kg/day for 104 weeks.

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

The NOEL has been taken as 7 mg/kg/day in the

rat in a 28 month study and a similar value could
have been deduced from shorter experiments.
3.3. Genetic toxicity testing
Negative results have been obtained in Ames,
CHO chromosome aberration and 3T3 cell transformation tests in vitro; a positive result was
obtained in an in vivo mouse bone marrow
micronucleus test (EMEA, 1997). The latter was
regarded as the same as the action of albendazole
sulphoxide (details not provided) and as consistent
with an aneugenic action (Authors note: common
to all benzimidazoles at appropriate concentrations; see discussion of genotoxicity in Section
5.2.3 below). EMEA concluded that albendazole
should be regarded as a potential mutagen and
that no level had been identified at which there
would be No mutagenic risk to consumers of
meat containing ALB residues. Scientific opinion
has changed since then, as it has been recognised
that there is a threshold concentration below
which aneuploidogenesis will not occur, so assessment of the risk of exposure to an aneugenic
substance must also take account of the concentration or dose involved. On that basis, it has been
stated by various independent expert groups that
conventional therapeutic use of ALB will not pose
a risk of aneuploidy in man (Committee on
Mutagenicity, 1996; Aardema et al., 1998); see
also the discussion of the genotoxicity of mebendazole, an analogous substance with a similar
action (Section 5.2.3.)

147

3.5. Reproduction toxicity testing

ALB had no effect on fertility in a threegeneration test in the rat at up to 20 mg/kg/day;
0.32-times the human dose per m2 (PDR, 2001a).
ALB had no effect in a maternal and fetal
toxicity test in the mouse at up to 30 mg/kg/day;
0.32-times the human dose per m2 (JECFA, 1989a;
PDR, 2001a).
ALB is a teratogen and causes fetal toxicity in
Segment II tests in the rat at doses
/7.5 mg/kg/
day, producing craniofacial, skeletal and visceral
defects; the NOEL is 5 mg/kg/day (JECFA, 1989b;
PDR, 2001a).
In a Segment II test in the rabbit, ALB 10 and
30 mg/kg/day caused maternal and non-specific
fetal toxicity (JECFA, 1989b).
There is extensive experience of ALB in pregnant food animals in which doses 10 mg/kg/day
have caused fetal death and teratogenic effects
(JECFA, 1989b).
JECFA (1989b) has published a table comparing cmax of ALB sulphoxide in various species in
which teratogenicity has been reported and in man
after a therapeutic dose of 400 mg. It shows that
fetal effects have been seen in several species in
association with a cmax of about 2.5 /6.6 mg/ml
(Authors note: probably misprint for mg/L)
compared to the Cmax in man of 0.16 mg/ml.
A formal Segment III test (peri- and postnatal
development) has not been reported but the
published three-generation test may be considered
an adequate substitute for it.
3.6. Other toxicity results

3.4. Carcinogenicity testing

In a three-generation test in the rat at up to 11.6
mg/kg/day, in which F3 animals were treated for
24 months there was no evidence of a carcinogenic
action (JECFA, 1989b; EMEA, 1997). A negative
result was obtained in another study in the rat at
400 mg/kg/day for 24 months; twice the human
dose per m2 (PDR, 2001a).
A carcinogenicity test in the mouse at up to 400
mg/kg/day for 24 months (0.21-times the human
dose per m2) (PDR, 2001a) gave a negative result.

ALB was not an acute skin or eye irritant

(JECFA, 1989b).
3.7. Toxicovigilance
The British toxicological surveillance system for
adverse actions of veterinary drug therapies
(SARSS, Veterinary Medicines Directorate, DEFRA, UK) does not contain any relevant reports
of harmful effects during clinical use of ALB
(Personal Communication Dr J Gray (2002):

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A.D. Dayan / Acta Tropica 86 (2003) 141 /159

Report from Convance Laboratories, UK, to

Janssen Research Foundation).
3.8. Veterinary experience
Albendazole is authorised for use in veterinary
medicine for the treatment of gastrointestinal
nematodes, lungworm (Dictyocaulus spp.), tapeworm (Moniezia spp.) and liver fluke (Fasciola
hepatica) in ruminant species. The recommended
dosages are 5 mg/kg for roundworms and tapeworms in sheep, 7.5 mg/kg for roundworms and
tapeworms in cattle and fluke in sheep and 10 mg/
kg for fluke in cattle. Albendazole sulphoxide is
also authorised for a similar spectrum of parasites
at the same dosages in ruminants and the albendazole pro-drug netobimin is authorised at dosages of 7.5 mg/kg for roundworms and
tapeworms in sheep and cattle and at 20 mg/kg
for fluke in sheep and cattle. Netobimin is
metabolically cyclized into the carbamate benzimidazole albendazole to which it owes its activity.
There is a general contraindication for the use of
these drugs in ewes at a dose of 7.5 mg/kg during
mating and for one month after rams are removed
and in cattle at dosages greater than those
authorised during the first month of pregnancy.
The slow dissolution of the poorly soluble
sulphides and sulphoxides limit their rate of
absorption and consequently extend their residence times in the body. Metabolic processes are
also important and the greater oxidative metabolic
capacity of cattle result in more rapid sulphoxidation and sulphonation (inactivation) compared to
sheep and largely accounts for the larger dosage in
cattle than sheep. In sheep the AUC for albendazole sulphoxide (61 mg.h/ml) was greater than that
achieved in cattle (22 mg.h/ml) following the same
dose (10 mg/kg) of albendazole. The proportions
of albendazole sulphoxide and albendazole sulphone appear to change if albendazole is given at a
low dose over a prolonged period of time since the
sulphoxide predominates if the drug is given in a
single dose but the sulphone predominates if the
drug is given in a sustained release device (Delatour et al., 1991a,b).
Congenital malformations resulting from the
administration of albendazole during early gesta-

tion in ewes have been reported. However, other

domestic species appear to be less sensitive to these
effects and administration of albendazole to cattle
during pregnancy is not contra-indicated as it has
not caused an increase in the incidence of congenital abnormalities in their offspring.

4. Overview

4.1. General
As already noted above in Section 2.1.3, albendazole is a long established medicine, widely used
for 20 years in man and animals. Its age means
that, although there are extensive preclinical
studies of many aspects of its pharmacology,
pharmacokinetics metabolism and toxicity in several species, the test protocols may not comply
with current standards and, in many instances, full
details of the results obtained are not in the public
domain.
On the other hand, there is very extensive
practical experience of the use of albendazole in
humans and farm animals and so many opportunities for adverse actions to be reported.
It is very important that review of Medline and
Embase and the principal public adverse event
sources (e.g. Davies et al., 1998; Dukes et al.,
2000), as well as the legally binding Summaries of
Product Characteristics for human and veterinary
medicines in Britain and the USA show few
adverse events associated with its use in man and
animals, other than those secondary to its therapeutic effect on certain parasites.
It is important, too, that in evaluating the
suitability of albendazole for administration to
food animals and so in considering the safety of
residues that will be consumed by the general
population, both JECFA (1989a) and EMEA
(1997) have found it reasonable to accept its
wide use. Further, EMEA (1997) based its acceptance of ALB on information that included a
calculation showing that ordinary consumers
might readily eat as much as 103% of the ADI
on a daily basis.

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

4.2. Pharmacokinetics and toxicity testing

The detail available in the pharmacokinetic,
drug metabolism and toxicity reports is limited in
most instances to summaries or to academic
investigations, neither of which is as comprehensive as full experimental reports. However, it is
apparent that regulatory agencies have seen fuller
accounts of studies and findings than were available to me and they were willing to accept the
information as appropriate for their evaluation of
ALB as a human medicine and for veterinary use.
None of them has stated that the toxicological
database should be regarded overall as inadequate.
The pharmacokinetics and metabolism of ALB,
as noted in Section 2.1.3 above, are qualitatively
similar in all species investigated, and there is no
indication that the quantitative differences have
prevented an adequate evaluation of the toxicity in
animals as a guide to risks to man.
4.3. Toxicological issues
Key points of toxicological concern arising from
the non-clinical information and relevant to the
purposes of the Discussion Meeting are:
. albendazole itself is a prodrug of the active
form albendazole sulphoxide
. metabolic activation and detoxification depend
on cytochrome P450 and flavin monoxoygenases, as well as standard Phase II conjugating enzymes
. the metabolism of APB in man depends in part
on P450s 1A1 and 3A4. It also induces its own
metabolism on prolonged administration. The
role of these enzymes has implications for
genetic and possibly ethnic variation, and as a
means by which drug and dietary interactions
might occur. Studies of age-related differences
in Phase I and Phase II metabolism have not
been reported
. the absorption of albendazole is poor and is
increased by food and especially fat in the diet
. there do not appear to be reports of comprehensive studies of the kinetics and disposition of
ALB and its metabolites in pregnant animals or
in breast milk

149

. safety pharmacology studies do not appear to

have been reported. It must be recognised that
there is no indication of harmful actions of this
type in man and animals despite many years of
extensive use of the drug, so the data should not
be regarded as of great importance.
. ALB is regarded as genotoxic on the basis of
unpublished results from an in vivo mouse bone
marrow micronucleus test (EMEA, 1997). It is
probably an aneugen. No studies have been
found that have explored directly whether this
represents a risk to humans under circumstances of therapeutic dosing but it has been
stated by an authoritative official advisory
Group that it is unlikely to pose a risk to
humans after conventional therapeutic use
(Committee on Mutagenicity, 1996).
. ALB is known to be a teratogen and a fetal
toxicant in experimental animals at doses that
produce peak plasma levels of the active form,
albendazole sulphoxide, from 5 to 16-times
greater than those found in adult humans given
a single therapeutic dose of the drug.
There do not appear to have been reports of a
teratogenic action in humans, not even in women
dosed during pregnancy (EMEA, 1997; PDR,
2001a).
Albendazole is permitted for use in pregnant
and non-pregnant food animals. Meat from them
is permitted for human consumption after a withholding period.

5. Mebendazole
CAS 31431-39-7
Mebendazole (MEB) (Fig. 3) is also a typical,
broad spectrum benzimidazole used for more than
20 years in human and veterinary medicine to treat
a variety of parasitic infestations. It is methyl 5benzoyl-1H-benzimidazol-2-yl-carbamate.
Dosage. In Britain (ABPI, 1999b) the recommended dosage for roundworms (Ascaris ), whipworms (Trichuris ) and hookworm (Ankylostoma
and Necator) is: Adults and children
/2 years 100
mg b.d. for 3 consecutive days. For pinworms
(Enterobius ) in adults and children
/2 years 100

150

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

mg once. It is strongly recommended that a second

100 mg dose be given after 2 weeks if reinfection is
suspected.
It is contraindicated in pregnancy.
Veterinary Usage. Approved in Britain for use in
sheep, cats and dogs, including lambs, puppies and
kittens and pregnant animals (NOAH, 2001).
It is believed to act by binding to and inhibiting
essential intracellular microtubule-dependent
transport processes in the parasite (Martindale,
1993b; Dollery, 1999b; EMEA, 1999, 2001).
5.1. Pharmacokinetics and metabolism
No single comprehensive review was found but
extensive summarised information was available in
Dollery (1999b), EMEA (1999, 2001) and PDR
(2001b); brief summaries are noted in the Hazardous Substances database of the USEPA (accessed
February 2002).
RIA and HPLC-UV or electrochemical detection analytical methods have been described,
suitable for use on blood and other fluids from
humans and animals (Dollery, 1999b).
5.1.1. Absorption, distribution and excretion
The very limited solubility of MEB in water and
organic solvents affects its absorption and behaviour in the body.
Oral absorption of MEB is poor in all species; it
has been reported as 5 /10% and 17 /22% in
healthy adult human volunteers after 1.7 mg 3HMEB, falling to 1/2% after a higher dose; broadly
similar results have been obtained in the rat
(Dollery, 1999b; EMEA, 1999, 2001).
In healthy adult humans, oral MEB 1.5 g gave
plasma levels
/5 mg/l. The same dose taken with a
fatty breakfast produced plasma levels of 27/42
mg/l (Dollery, 1999b; EMEA, 1999). The very
limited bioavailability, which is mainly due to the
poor solubility of the drug in conventional tablets,
has probably been the rate-limiting factor in
studies of absorption and kinetics after oral
administration of that dosage form (Martindale,
1993b; Dollery, 1999b).
In patients with echinococcosis and other parasitic diseases, the peak plasma level after a single
or multiple oral doses has shown marked inter-

Fig. 3. Mebendazole.

individual variation but has always been higher

than in healthy subjects, even up to 500 mg/l
(Dollery, 1999b; EMEA 1999, 2001). The half
life of elimination has shown similar variation
between healthy and diseased humans, ranging
from 2.8 to 9 h (Dawson et al., 1985; Witassek et
al., 1981; Braithwaite et al., 1982). Levels in cyst
fluid in echinococcosis behave similarly. Much
higher plasma levels were reported in one patient
with cholestasis (Dollery, 1999b).
MEB undergoes extensive first pass metabolism
in the intestinal wall and liver in man and animals
(Dollery, 1999b; EMEA, 1999) and almost no
parent drug is excreted as such.
Clearance is predominantly as metabolites in
bile and urine; there is usually much unchanged
drug in faeces.
In humans, the VD of MEB is /1 l/kg and it is
95% protein bound. The concentration in plasma
is always higher than in CSF or cyst fluid (about
10-fold difference); in the ratio blood:liver is 0.79
(Dollery, 1999b).
The clinical pharmacokinetics of MEB has been
summarised by Edwards and Breckenridge (1988).
Protein binding in man is said to be about 90%
(Janssen report R-017635, 2001).
5.1.2. Metabolism
This occurs predominantly in the liver
(Gotschall et al., 1990). In man the major metabolites in plasma result from reduction of the ketogroup to a hydroxyl function and independent
decarbamylation of the imidazole ring (Dollery,
1999b; EMEA, 1999). Urine contains very small
amounts of both those metabolites and about four
times as much unidentified, conjugated metabolites.
Metabolism in the rat, dog and pig and in other
food animals is comparable, with relatively small
quantitative differences between species in the

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

proportions of the various metabolites and conjugates. The rat is a good model of man (Dollery,
1999b; EMEA, 1999); metabolism in the rat, dog
and pig is similar to that in man (Janssen Report N
4952). Many metabolites have not been individually identified; they are very probably conjugates
(Janssen Report N 4952; Dollery, 1999b).
The metabolites lack antiparasitic activity
(PDR, 2001b).
Co-administration of cimetidine and MEB to
humans leads to an increased plasma level of
MEB, probably due to inhibition of hepatic first
pass cytochrome P450-mediated metabolism of the
MEB (Bekhti and Pirotte, 1987)
Authors note: The enzymes responsible for
metabolism and conjugation have not been identified. General experience suggest that decarbamylation probably results from the action of wide
range of esterases. It is possible that the ketoreduction is due to a number of enzymes. The
interaction with cimetidine in humans suggest that
cytochrome P450 3A4 may be important in the
metabolism of MEB.
There do not appear to have been studies of the
effects of repeated dosing on the kinetics of the
drug but as the major limiting factor has been its
very poor absorption, it is unlikely that there will
be appreciable accumulation, or enzyme induction
or inhibition.

5.1.3. Comments by author

Like ALB, the extent of the publicly available
work on the ADME of MEB is very limited,
although it is apparent that extensive detailed
studies in a variety of species have been made
available to regulatory agencies (see reports by
EMEA, 1999, 2001; ABPI, 1999a and PDR,
2001a, for example).
The rat is a good model of man in terms of
overall kinetics and metabolism.
The important points appear to be that oral
absorption of the tablet formulation is very limited
and that the drug undergoes extensive and rapid
first pass metabolism to inactive products. Both of
these factors probably contribute extensively to
the considerable variability of the plasma levels in
infected humans and animals.

151

Clearance depends both on metabolism in the

liver and excretion mainly in the bile. It is possible
that severe liver disease may result in higher
plasma levels of the parent drug and its metabolites.
It is known that co-administration of MEB
tablets with a fatty meal greatly enhances absorption and increases the peak plasma level but there
do not appear to have been formal publications
about the possible effects of repeated doses, age
and genetic or ethnic variation on its kinetics.
Excretion in breast milk has not been reported
but metabolites are likely to pass into milk.
5.2. Toxicity testing
No publicly available accounts of toxicity test
results were found but the official reports by
EMEA (1999, 2001) and the implications of the
Summaries of Product Characteristics (ABPI,
1999b; PDR, 2001b) are that many formal study
reports have been reviewed and considered acceptable by regulatory agencies.
The following summary is based entirely on the
publications by EMEA (1999, 2001).
5.2.1. Acute toxicity
Oral LD50
Wistar rat

male 1434 mg/kg

female 714 mg/kg
Other rodents and rabbits

/1280 mg/kg
Principal finding was diarrhoea and Emesis
(Authors note: I believe the latter may be a rear
regurgitation as rodents and rabbits are not
normally considered capable of vomiting).
5.2.2. Repeated dose tests
Wistar rats received MEB in the diet for 13
weeks, males up to 127.3 mg/kg/day and females
up to 151.6 mg/kg/day. There were some deaths,
retardation of weight gain, anaemia and increased
serum alkaline phosphatase in the top-dose group
and evidence of testicular damage in those males
and the next group on 32.1 mg/kg/day. Relative
liver weight in both groups was increased and
there was hepatocyte vacuolation and swelling and
bile duct proliferation.

152

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

The NOEL was 7.8 and 8.4 mg/kg/day in males

and females, respectively.
In a 13-week oral test in the dog at up to 10 mg/
kg/day (dosed only 6 days/week), there was also
some anaemia and increased serum levels of alkaline phosphates, bilirubin, cholesterol and total
protein. The NOEL was 2.5 mg/kg/day.
In another experiment, Beagle dogs were given
up to 40 mg/kg/day as capsules for 24 months. No
consistent dose-related effect was produced. The
ECG was not affected.
5.2.3. Genetic toxicity
Many studies have been reported because of
interest in the significance for human risk assessment of the ability of various benzimidazole antiparasitic drugs to act as mitotic spindle poisons
and so to produce aneuploidy in in vitro test
systems.
MEB has given clear negative results in Ames
tests using strains TA 1530, 1535, 1537, 1538 and
97. It is reported as having produced clastogenicity
in cultured cells and in bone marrow cells from
dosed rats (details not provided). It has also been
shown to affect dividing human lymphocytes in
vitro, producing a dose-related increase in binucleate cells (taken as an indirect indicator of aneuploidogenic potential) and subsequently confirmed
as due to aneuploidy; the No effect concentration
was
/85/115 ng/ml. An oral in vivo micronucleus test in the mouse gave a negative result at up
to 40 mg/kg (regarded as too low a dose). There
were also negative results in 4 dominant lethal tests
in the mouse, in a spermatocyte test and in an F1
translocation test, i.e. it was not a germ cell
mutagen.
In further in vivo oral, bone marrow micronucleus tests in the mouse at up to 2000 mg/kg,
MEB did produce positives at doses
/10 mg/kg,
which were shown to be due to aneuploidy.
EMEA (1999, 2001) has considered and approved MEB as a veterinary drug for use in foodproducing animals. It accepted an ADI of 0.0125
mg/kg/day and set an MRL on that basis but not
for use in animals from which milk was obtained
for human consumption.
The official British government Committee on
Mutagenicity has discussed the question of aneu-

ploidy and the benzimidazoles, including MEB

(Committee on Mutagenicity, 1996). Its overall
assessment was that MEB (and ALB) were unlikely to represent a risk of aneuploidy in humans
because of the existence of a threshold exposure
below which that effect would not occur and the
doses and plasma levels following therapeutic use
in animals and man were much lower. A similar
conclusion was reached by an independent group
of experts (Aardema et al., 1998) and in a special
assessment report commissioned by the Janssen
Research Foundation (Gray, 1999).

5.2.4. Reproduction toxicity

MEB has been shown to be a teratogen at
certain dose levels in the rat but not in the rabbit
(Dollery, 1999b; EMEA, 1999).
In the rat, the NOEL for fetotoxicity and
teratogenicity has been 10 mg/kg/day; skeletal
and limb abnormalities were produced. Rabbits
have been given up to 40 mg/kg/day during
gestation without producing fetal damage. MEB
has not been shown to be teratogenic in pigs, dogs,
cats, sheep and horses (EMEA, 1999, 2001).
In the mouse, MEB 10 mg/kg/day during
gestation caused maternal toxicity, fetal deaths
and malformations (EMEA, 2001).
MEB has not affected fertility in a one-generation and a limited three-generation test in the rat
(EMEA, 1999).
The NOEL in a peri/post-natal study in the rat
was 10 mg/kg/day.
No work was found on the kinetics of MEB in
pregnancy.
Authors comments: MEB causes fetal toxicity
and teratogenicity in the rat but not in other
species, like other benzimidazole drugs. There has
been a clear demonstration of a NOEL in the
susceptible species, the rat, at 10 mg/kg/day during
gestation.
The Datasheet for its use in man in Britain and
the USA notes that it is contraindicated in
pregnancy (ABPI, 1999b; PDR, 2001b) and,
from the veterinary viewpoint, EMEA (1999,
2001) has maintained a ban on its use in animals
from which milk or meat for human consumption
will be obtained (except after a 14-day withholding

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

period), whilst permitting its use in pregnant sheep

and cattle.
5.2.5. Carcinogenicity testing
Inadequate carcinogenicity tests in the rat and
mouse did not show an oncogenic action in
animals given up to 40 mg/kg/day for 23/24
months (EMEA, 2001).
5.2.6. Toxicovigilance information
The British toxicological surveillance system for
adverse actions of veterinary drug therapies (Suspected Adverse Reactions Surveillance Scheme
(SARSS), Veterinary Medicines Directorate, DEFRA, UK) does not contain any relevant reports
of harmful effects during clinical use of PZQ
((Personal Communication Dr J. Gray (2002):
Report from Covance Laboratories, UK, to Janssen Research Foundation).
5.2.7. Veterinary experience
Mebendazole is effective against gastro-intestinal nematodes in horses, donkeys, sheep, dogs
and cats; lungworm in donkeys and sheep and
tapeworms in sheep (Moniezia spp.) dogs and cats
(Echinococcus and Taenia spp.). Dosage recommendations vary from 5 mg/kg for nematode
infections in horses to more than 50 mg/kg in
dogs and cats for mixed worm infections. Furthermore, it is recommended for the treatment of
Dictyocaulus arnfieldi (lungworm) in donkeys and
mixed worm infections in dogs and cats that
treatment should be repeated for five consecutive
days. In donkeys high doses are contraindicated
during the first four months of pregnancy but
there is no such restriction on its use in dogs or
cats. There is a general meat withdrawal period of
7 days and milk from treated sheep should not be
used for human consumption until 24 h after
treatment. Granule, suspension, paste and tablet
preparations are available and mebendazole is also
combined with flukicidal drugs for the treatment
of sheep with fluke and worm infections.
5.3. Conclusions and toxicological issues
Like albendazole, mebendazole was developed
and introduced into human and veterinary medi-

153

cine many years ago. There is relatively little fully

reported information about its pharmacokinetics
and especially about its toxicity but more extensive
data have been reviewed by several regulatory
agencies and the drug has been widely accepted for
human use with the proviso that it should not be
given to pregnant women or to children B/2 years
old.
Key points about the available information are:
. Mebendazole is active against a number of
species of parasite.
. It is poorly absorbed, probably because of its
insolubility in solid dosage conventional tablet
formulations, and it undergoes rapid first pass
metabolism.
. It is rapidly inactivated by metabolism involving keto-reduction and decarbamylation, followed by conjugation. Details of these steps
have not been well explored. Excretion is
predominantly in bile. The blood level is low
but measurable. The rat is a reasonably good
model of man. Blood levels have shown considerable inter-individual variation, probably
because of variability in release and absorption
more than in metabolism.
. Details of its toxicity testing are sparse but
more information appears to have been reviewed by various official agencies than has
been released into the public domain.
. It has low systemic toxic potential but high
doses can cause anaemia and liver damage.
. It is a recognised teratogen in the rat and
mouse. There is a clear NOEL for this experimental effect.
. MEB causes aneuploidy in in vitro and in vivo
experiments but this effect is not considered to
be a risk to humans receiving conventional
therapy.
. Major deficiencies in the published experimental data are:
incomplete examination of pharmacokinetics
and metabolism, especially of its behaviour
during pregnancy and whether it penetrates
into milk;
limited study of potential drug interactions
and of genotypic and phenotypic factors that
might affect its kinetics;

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

154

absence of reports of its safety pharmacology

testing. It is recognised that there are no
indications that such information is important because there has been no clinical
indication of harmful effects of the types so
revealed; and
reportedly inadequate carcinogenicity testing.

Fig. 4. Praziquantel.

dosage for the latter groups of young animals

(NOAH, 2001).
6.1. Pharmacokinetics and metabolism

6. Praziquantel
CAS 55268-74-1
Praziquantel (PZQ) (Fig. 4) is a pyrazinoisoquinoline available for human and veterinary use
against various cestode and trematode parasites,
most notably schistosomes, since about 1980.
Chemically
it
is
2-cyclohexylcarbonyl1,2,3,6,7,11b-hexahydropyrazino{2,1-a) isoquinolin-4-one. Only the (/) enantiomer is active.
Its mode of action is not certain but it rapidly
causes tegumental damage and paralytic muscular
contraction of parasites, followed by their death
and expulsion, possibly due to an action on
parasite GSH and the intracellular calcium level,
with secondary effects on metabolism and antigenicity (Dollery, 1999c).
Dosage. PZQ is not licensed in Britain for
human use but it is approved in the USA and
many other countries.
Martindale (1993c) notes:
Schistosomes

20 mg/kg with food, every

4/6 h, on one day as three
doses
Clonorchis and
25 mg/kg three times on one
Opisthorchis
day
Tape worms
10/25 mg/kg as a single
dose
The PDR (2001c) describes the same regimes.
In the USA (PDR, 2001c) it has been placed in
Pregnancy Category B, i.e. administer to pregnant
women only if essential.
Other therapeutic regimes have been described.
Veterinary Use. Approved in Britain for use in
adult cats and dogs of both sexes, including kittens
and pups, with no reduction in the standard

The pharmacokinetics has been generally reviewed in EMEA (1996) and Dollery (1999c).
6.1.1. Absorption, distribution and excretion
PZQ has limited aqueous solubility.
There is a good HPLC technique for the
racemate, suitable for application to plasma and
other samples from animals and man (Dollery,
1999c). A chirally sensitive technique for resolving
the isomers and suitable for application to clinical
samples has not been reported.
Absorption is considered to be good at 75 /
100% of an oral dose in rat, dog, monkey and
man; tmax is reached after 30 /120 min in animals
and up to 3/4 h in humans. There is considerable
inter-individual variation for unknown reasons in
the rate of absorption and clearance, so cmax, tmax
and AUC show wide ranges (Dollery, 1999c). A
carbohydrate-rich meal enhances absorption in
man (Mandour et al., 1990). Co-administration
of chloroquine and pre-administration of carbamazepine and phenytoin may reduce the bioavailability of PZQ (Bittencourt et al., 1982;
Masimirembwa and Hasler, 1994).
There is extensive first pass metabolism of PZQ
in all animals in the liver to mono- and dihydroxylated derivatives, many of which are conjugated. A few of the metabolites possess some but
weaker antiparasite activity but PZQ itself is the
important therapeutic agent (Buhring et al., 1978;
Andrews et al., 1983).
Overall clearance is rapid, with a t1/2el of
unchanged PZQ of 1/2 h in most species and of
metabolites of 3 /8 h (EMEA, 1996; Dollery,
1999c). Clearance of metabolites, which is limited
by the rate of metabolism, is slower but even in

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

man metabolites are completely cleared by 4 days

after an oral dose.
VD has not been reported; PZQ is 80% bound to
plasma proteins in animals and man.
Excretion is as metabolites and some parent
drug in urine; metabolites in urine accounted for
38 and 66% of an oral dose in rat and dog,
respectively, within 8 h and about 15% in bile
(EMEA, 1996); in man about 80% of a dose is
excreted in urine.
PZQ and its principal metabolites are found in
human milk at levels about 25% of those in plasma
and following the same rapid time course (Putter
and Held, 1978).
6.1.2. Metabolism
First pass metabolism in the liver is rapid; 15
min after an oral dose of 14C[PZQ], the serum
radioactivity consisted of 99% metabolites in the
rat, 84% in the dog and a similar proportion in
humans.
The enzyme(s) responsible has not been definitely identified but it is likely at least to include a
member of the P450 3A4 family in the lamb and
rat, judged by selective inhibition experiments
(Masimirembwa et al., 1994). The important
isozyme in man has not been described. It is likely
that the reported effect of co-administration of
ALB in increasing the plasma level of PZQ is due
to inhibition of P450 enzymes (Homeida et al.,
1994).
The principal metabolites in animals and man
are mono- and di-hydroxy derivatives of PZQ
(Dollery, 1999c). Several enantiomers exist. As
they appear to be formed in all species, the toxicity
testing will have covered their effects.
6.1.3. Comment by author
The pharmacokinetics and metabolism of PZQ
have been quite extensively reported in the open
literature. There is a considerable degree of
similarity between laboratory species, the sheep
and man, showing that the rat, for example, is a
good model of humans.
The implication of the oxidative metabolism
probably via cytochrome P450 3A4 for genotypic
and phenotypic variations appears not to have
been explored. On the other hand, there are no

155

major reports of adverse actions or grossly altered

pharmacokinetics due to co-administration of
other drugs, such as those affecting the P450
system.
In a formal sense, the kinetics of PZQ during
gestation in animals or man have not been
explored, but the high VD suggest that both the
parent drug and its metabolites will penetrate the
placenta.
6.2. Toxicity testing
It is fortunate that the scientists involved in the
original development of PZQ published extensive
accounts of the principal toxicological findings in
a very extensive series of reports in the open
literature; Frohberg and Schulze-Schencking
(1981), Frohberg (1982, 1984, 1989). The more
important additions since those reports have been
further investigations of genotoxicity. Amongst
the latter, the summary from EMEA (1996) does
mention the more significant findings.
6.2.1. Acute toxicity
Oral LD50

mouse
rat
rabbit
from Frohberg (1982).

/2560 mg/kg
/2840 mg/kg
/1050 mg/kg

6.2.2. Repeated dose toxicity

No particular toxic effects were noted in rats
treated with PZQ up to 1000 mg/kg/day for 4
weeks and dogs with up to 180 mg/kg/day for 13
weeks (Frohberg, 1982, 1984). EMEA (1996)
reports the NOELs for those experiments as */
rat 33 mg/kg/day and dog 60 mg/kg/day.
6.2.3. Genetic toxicity
A very large number of studies has been
described in the initial reports and subsequently
by many independent investigators. As EMEA
(1996) has concluded, the findings of the interpretable studies have convincingly shown that
PZQ lacks mutagenic potential for man.
An earlier report by a distinguished body of
international experts (International Commission
for Protection against Environmental Mutagens

156

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

and Carcinogens (ICPEMC)) also concluded that

if PZQ had any mutagenic effect in man, which
was very improbable, it would be too small to be
detected in the treated population (Kramers et al.,
1991).
6.2.4. Reproduction toxicity
PZQ has not shown harmful effects in Segment I
(fertility) and Segment II (fetal and maternal
toxicity and teratogenicity) experiments at up to
300 mg/kg/day. A limited Segment III test (peri/
post-natal toxicity) also showed no harmful effect
of PZQ 300 mg/kg/day in the dams or their pups
but the former were only dosed on D15 /21 of
gestation and not throughout lactation to weaning
as is now common practice.
PZQ is approved for use in cats and dogs,
including pregnant animals and in sheep, potentially including pregnant animals (EMEA, 1996).
6.2.5. Carcinogenicity
The drug was not carcinogenic in the rat or
hamster treated for 104 and 80 weeks, respectively
(Frohberg, 1982, 1984, 1989). It also did not
accelerate tumorigenesis in a putative short-term
test in which Syrian hamsters pre-treated with
dimethylnitrosamine and infected with O. viverrini
were subsequently given PZQ kg/kg on 55 occasions and followed for 80 weeks (Thamavit et al.,
1992); the regime was intended to explore the
potential influence of PZQ on tumorigenesis in the
damaged liver.
6.2.6. Toxicovigilance information
The British toxicological surveillance system for
adverse actions of veterinary drug therapies
(SARSS, Veterinary Medicines Directorate, DEFRA, UK) does not contain any relevant reports
of harmful effects during clinical use of PZQ
(personal communication Dr J Gray, 2002: Report
from Covance Laboratories, UK, to Janssen
Research Foundation).
6.2.7. Veterinary practice
Praziquantel is used in veterinary practice for
the treatment of immature and mature tapeworms
in dogs and cats. It is indicated for the treatment
of Echinococcus granulosus , Echinococcus multi-

locularis, Taenia multiceps , Taenia hydatigena ,

Taenia ovis , Taenia pisiformis , Taenia taeniaeformis and Dipylidium caninum . The tablet formulation is administered at a dose of 5 mg/kg orally.
An injectable preparation is available at a variable
dose of 3.5 /7.5 mg/kg, with smaller animals
receiving a relatively larger dose because of their
higher metabolic rate. The injectable formulation
can be given either subcutaneously or intramuscularly and a brief pain response may be elicited if
given subcutaneously. It is contraindicated in
hound breeds by injection. There is also a spoton preparation for transcutaneous delivery to cats
at a dose of 8 mg/kg. Several combination
preparations containing praziquantel with pyrantel embonate and febantel are also available for
combined tapeworm and round worm infestations.
Praziquantel is commonly used off label in veterinary practice to treat tapeworm infections in
exotic pets, birds and small mammals.

6.3. Conclusions and authors comments

Like the other drugs mentioned here, PZQ has
been extensively studied over the years, although
the majority of the reported investigations were
completed some while ago, when accepted protocols will have lacked some of the refinements now
regarded as conventional. However, review of the
original reports and their evaluation by official
agencies (EMEA, 1996; PDR, 2001c) have all
concluded that it lacks significant toxic potential
in laboratory experiments. In human beings, too,
its adverse event profile (Martindale, 1993c; PDR,
2001c) has comprised only mild, transient acute
actions.
EMEA has accepted the use of PZQ in sheep
without the need to set an MRL (EMEA, 1996).
Non-clinical information it might be helpful to
have available comprises:
. more complete account of kinetics in pregnancy
and weaning,
. fuller exploration of the enzymes involved in its
metabolism, and
. more comprehensive account of its safety pharmacology.

A.D. Dayan / Acta Tropica 86 (2003) 141 /159

It is realised that none of these investigations is

likely to have any effect on its well proven clinical
use, so the information ought not to be regarded
as essential.

Acknowledgements
I am most grateful for the kindness and help of
the following in providing extensive information
about the drugs and especially for making previously unpublished company reports available:
Dr M. Hanisch, Bayer AG, Dr J. Horton, GSK
plc, Dr K. Troester, Dr Merck KG, and Dr P.
Vanparys, Johnson and Johnson Inc. Professor Q.
McKellar, SARI, Moredun, and Mr A. Gray, UK
Veterinary Medicines Directorate, generously gave
invaluable help and information. It is no less a
pleasure to thank Dr D. Engels, WHO, and
Professor P. Folb, Capetown University, RSA,
for their advice and assistance and WHO (TDR)
for making preparation of this review possible.

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