Br. J. clin.

Pharmac (1982), 14, 453-455

THE PHARMACOKINETICS AND BIOAVAILABILITY

OF MEBENDAZOLE IN MAN: A PILOT STUDY USING
[3H]-MEBENDAZOLE
M. DAWSON, R.J. ALLAN & T.R. WATSON
The Department of Pharmacy, The University of Sydney, Sydney, N.S.W. Australia

Following the intravenous administration of a tracer dose (1.7 ,ug) of [:'H]-mebendazole to a man, an
elimination half-life of 1.16 h was observed and the volume of distribution was calculated to be 2.03
1/kg. After oral administration of the same dose, an elimination half-life of 0.74 h was observed. The
bioavailability of mebendazole from the solution was found to be 17%.

Introduction
The anthelmintic mebendazole has been the object of
a number of investigations with regard to its potential
as a chemotherapeutic agent for the treatment of
echinococcosis (Beard etal., 1978; Bekhti etal., 1977)
and onchoceriasis (Rivas-Alcala et al., 1981). The
variability of the clinical response in patients treated
with this drug could be related to its poor bioavaila-
bility, and the consequent difficulty of achieving and
maintaining effective blood levels.
The very low solubility of mebendazole has pre-
vented its formulation for intravenous therapeutic
administration, so that no measure of its half-life, and
no real estimate of its bioavailability has been made
using the standard method of comparing blood con-
centrations v time, following oral and intravenous
dosing.
In this study, a tracer dose of [:3H]-mebendazole
was administered to a human volunteer, both intra-
venously and orally, to determine the actual half-life
and bioavailability of the drug.
Methods
[PH]-mebendazole (specific activity 6.78 Ci/mmol),
and ['4C]-mebendazole (specific activity 2.57 mCi/
mmol) was donated by Janssen Pharmaceutica,
Belgium. A 0.6 Am sterile solution of [:3H]-mebenda-
zole containing 0.25% dimethyl sulphoxide in normal
saline was prepared. An indwelling cannula was
inserted into a vein in the left forearm of a healthy
male volunteer (76 kg, 1.83 m) who had taken no
other drugs for 1 week prior to the study. After
fasting overnight, 10 ml of the sterile [:3H]-mebenda-
zole solution was injected into a suitable vein in the
right arm over a period of 1 min.
0306-5251/82/090453-3 $01.00
Blood samples (20 ml) including a blank, were
withdrawn at appropriate times and transferred to
heparinised tubes. The blood samples were centri-
fuged and the plasma stored at -20°C.
A similar procedure was followed after oral
administration of 10 ml of the same solution. The
plasma samples were spiked with aliquots of [14C]-
mebendazole as an internal standard, and each
sample was extracted with 2 x 10 ml portions of
diethyl ether. The combined ether layers were
evaporated to dryness and the residue dissolved in
100 ,.I of dimethyl sulphoxide. An aliquot of each
extract was fractionated by reversed phase h.p.l.c.
using a 15 cm column packed with 5 ,um LiChrosorb
RP8 (Merck) material. The mobile phase used was
55% methanol in 0.05 M aqueous ammonium phos-
phate buffer (pH 7.0). The flow rate was maintained
at 1 ml/min, and a fixed wavelength (254 nm) detector
was used.
The effluent corresponding to the mebendazole
peak was collected and dissolved in 10 ml of scintilla-
tion cocktail (Instagel, Packard). Each vial was
counted to 1% statistical precision in a liquid scintilla-
tion counter operating in the :H/'4C dual channel
mode.
The d.p.m. attributable to [:H]-mebendazole in
each sample was calculated and the results shown
graphically in Figure 1 have been corrected for
extraction and fractionation losses by using the
d.p.m. obtained for the ['4C]-mebendazole internal
standard.
The data obtained, following intravenous adminis-
tration, was fitted to a two-compartment model, and
that obtained following oral administration, was
fitted to the one-compartment model.
The bioavailability (F) of 17% was calculated by
© The Macmillan Press Ltd 1982
454 M. DAWSON, R.J. ALLAN & T.R. WATSON
the application of the following formula:
F= AUCoral tI/f2
AUC..v tl,13 app.
Results
After intravenous administration, mebendazole was
rapidly distributed, the volume of distribution (Vd,,)
was calculated to be 2.03 1/kg and the elimination
half-life (ty,fl) was 1.16 h.
No absorption phase was observed after the same
dose of the drug had been administered orally (see
Figure 1) and the elimination half-life (tl/2 app.) was
calculated to be 0.74 h.
Discussion
These preliminary results are the first determination
of the bioavailability and true half-life of
mebendazole in man. Other studies (Braithwaite et
al., 1982; Munst et al., 1980; Witassek et al., 1980) in
which longer half-life values (2-8 h) were observed
used large oral doses of mebendazole (circa 0.5 g),
and probably measured the absorption half-life
rather than the elimination half-life.
In this study, the amount of mebendazole adminis-
tered (1.7 ,ug) was well below its saturation solubility
in the vehicle (normal saline) and, as no absorption
phase was observed, it has been assumed that rapid
and complete absorption of the dose occurred.
Animal studies in our laboratories have shown that
mebendazole is extensively metabolised by the liver
and eliminated in the bile. In rats, approximately
85% of an intravenous dose is eliminated in the bile.
We have also recovered mebendazole metabolites
from human bile samples.
Brugmans et al. (1971), after oral administration of
small doses (0.1 mg/kg) of ['4C]-mebendazole, found
less than 10% of the dose eliminated in the urine of
human subjects.
These factors, together with the very short elimina-
tion half-life indicate that the drug is probably under-
going rapid first pass metabolism and elimination
and, as a consequence, the low bioavailability of
mebendazole observed when it is given in therapeutic
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E
0)
N
co
(0
E
A102
'a
I 0
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Time (h)
Figure I Plasma level-time course of mebendazole
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