The bioavailability of griseofulvin from microsized and ultramicrosized tablets in nonfasting volunteers


Bijanzadeh, M.; Mahmoudian, M.; Salehian, P.; Khazainia, T.; Eshghi, L.; Khosravy, A.

Indian Journal of Physiology and Pharmacology 34(3): 157-161

1990


Tablets of either microsized or ultramicrosized griseofulvin (2 x 125 mg), were administered to 6 healthy volunteers of either sex just before a breakfast containing 4o g. of butter. The plasma concentration of griseofulvin were determined 1, 3, 5, 7, 9, 24, and 32 h. after dosing using a spectrofluorometric method, and pharmacokinetic parameters (Cp max, t max, AUC 0 - greater than 32) were calculated. These parameters were found to be; Cp max = 0.0.681 +/- 0.1 mu/ml, t max. = 2.51 +/- 0.33 h. and AUC = 14.14 +/- 2.33 micrograms h/ml for microsized tablets and Cp max = 0.80 +/- 0.08 +/- g/ml, t max = 2.44 +/- 0.54 and AUC = 16.25 +/- 1.16 microgram h/ml for ultramicrosized tablets. Our results show that mean peak plasma level and AUC (0 - greater than 32) are only slightly higher for the ultramicrosized preparation and the time to peak plasma level is similar in two preparations. Therefore, it is concluded that coadministration of griseofulvin with food will tend to reduce the difference between the bioavailability of the two type of preparations.

Indian
.1
Physiol
Pharmacol
1990;
34(3):
157-61
THE
BIOAVAILABILITY
OF
GRISEOFULVIN
FROM
MICROSIZED
AND
ULTRAMICROSIZED
TABLETS
IN
NONFASTING
VOLUNTEERS
M.
BIJANZADEH,
M.
MAHMOUDIAN,*
P.
SALEHIAN,
T.
KHAZAINIA,
L.
ESHGHI
AND
A.
KHOSRAVY
Pharmaceutical
Research
Center,
P.O.Box
13185-877
Tehran,
Iran
(
Received
on
July
5,
1990
)
Abstract
:
Tablets
of
either
microsized
or
ultramicrosized
griseofulvin
(2x125mg),
were
administered
to
6
healthy
volunteers
of
either
sex
just
before
a
breakfast
containing
4o
g.
of
butter.
The
plasma
concentration
of
griseofulvin
were
determined
1,
3,
5,
7,
9,
24,
and
32
h.
after
dosing
using
a
spectrofluorometric
method,
-and
pharmacokinetic
parameters
(Cp
max,
t
max,
AUC
0
—>
32)
were
calculated.
These
parameters
were
found
to
be;
Cp
max
=
0.0.681
±
0.1
p/ml,
t
max
=
2.51
±
0.33
h.
and
AUC
=
14.14
±
2.33
deg
hind
for
microsized
tablets
and
Cp
max
=
0.80
±
0.08
±g/ml,
t
max
=
2.44
±
0.54
and
AUC
=
16.25
±
1.16
sg
h/rni
for
ultramicrosized
tablets.
Our
results
show
that
mean
peak
plasma
level
and
AUC
(0
—>
32)
are
only
slightly
higher
for
the
ultramicrosized
preparation
and
the
time
to
peak plasma
level
is
similar
in
two
preparations.
Therefore,
it
is
concluded
that
coadrninistration
of
griseofulvin
with
food
will
tend
to
reduce
the
difference
between
the
bioavailability
of
the
two
type
of
preparations.
Key
words
:
griseofulvin
bioavailability
microsized
&
ultramicrosized
tablets
INTRODUCTION
Griseofulvin
an
orally
administered
antifungal
agent,
is
used
in
the
treatment
of
mycotic
diseases
of
the
skin,
hair
and
nails.
Because
of
its
poor
water
solubility,
oral
administration
of
this
drug
may
be
subject
to
variable
and
incomplete
absorption.
In
order
to
improve
oral
absorption
tablets
and
capsules
are
formulated
to
contain
microsize
crystals
of
griseofulvin.
Erratic
and
incomplete
absorption
with
these
formulations
is
still
possible
as
shown
by
the
sensitivity
of
griseofulvin
bioavailability
to
the
dissolution
rate
of
the
tablets
(1,
2).
Recently
products
have
been
formulated
with
the
drug
dispersed
in
polyethylene
glycol
6000
(3,
4).
The
labeling
of
these
commercially
available
"Ultramicorsize"
formulations
indicates
that
the
efficiency
of
nonfasting
volunteers
absorption
from
the
ultramicrocrystalline
griseofulvin
is
approximately
twice
that
of
the
conventional
microsize
griseofulvin
(5,
6)
permitting
oral
administration
of
half
as
much
griseofulvin
per
tablet.
Since
griseofulvin
tablets
is
usually
administered
with
food
and
the
absorption
of
this
drug
from
the
gastrointestinal
tract
is
substantially
increased
by
coadministration
with
a
fatty
meal
(7),
the
present
work
was
carried
out
to
investigate
the
effect
of
food
upon
the
bioavailability
of
the
drug
from
microsize
and
ultramicrosize
tablets.
METHODS
Formulation
:
One
commercial
microsize
griseofulvin
tablet
available
in
Iran
(Daru
Pakhsh
Co.)
and
one
ultramicrosize
griseofulvin
tablet
(Wander
Co.
Switzerland)
were
used.
*Corresponding
Author
158
Bijanzadeh
et
al
Bioavailabilability
:
Griseofulvin
were
administered
to
6
healthy
volunteers
(one
female
and
five
males;
age,
26
to
31
yrs;
weight,
33
to
61
kg.)
just
before
a
breakfast
containing
40g
to
butter.
Before
the
study
the
participants
were
given
a
clinical
examination
to
ensure
they
were
healthy.
All
of
the
subjects
were
prohibited
from
taking
medicines
and
alcoholic
beverages
from
7
days
before
the
drug
administration
to
the
end
of
the
test.
Each
'subject
took
two
tablet
orally
with
200
ml
of
water
and
then
breakfast
was
served.
Blood
samples
(10m1)
were
obtained
at
1,
3,
5,
7,
9,
24,
and
32
h.
after
drug
administration
and
the
plasma
samples
were
kept
frozen
at
C
until
assayed.
Model
independent
pharmacokinetics
parameters
[Cp
max,
t
max,
AUC
(0
—>
32)]
were
calculated
from
the
Plasma
concentration
of
griseofuvlin
at
various
times.
The
study
was
repeated
after
15
days
using
the
same
volunteers,
who
now
consumed
the
other
type
of
tablets
than
those
used
in
previous
study.
Assay
:
The
plasma
griseofulvin
concentration
was
determined
by
a
spectrofluorometric
method
described
previously
(8).
The
method
was
modified
slightly;
to
1.0
ml
of
plasma
in
a
stoppered
test
tube
was
added
10
ml
of
ethanol
1%
followed
by
10
ml
of
anhydrous
ether.
The
test
tube
was
shaken
for
1
min.
A
9
ml
aliquot
of
the
ether
layer
was
transferred
to
a
10
ml
test
tube
and
evaporated
to
dryness
with
nitrogen.
The
residue
was
dissolved
10
2.5
ml
of
80%
methanol
(V/V)
and
shake
for
20
min.
The
fluorescence
was
read
in
a
spectrofluorometer
(Perkin
Elmer)
with
the
following
settings
:
excitation
wavelength,
300
nm;
detection
wave
length,
420
nm.
RESULTS
Figures
1
and
2
show
the
serum
concentration
-time
curves
of
griseofulvin
in
healthy
volunteers
after
oral
administration
of
microsize
and
ultramicrosize
preparations
respectively.
The
bioaviilability
of
griseofulvin
from
ultramicrosize
tablets
is
more
uniform
than
that
of
microsize
tablets
as
indicated
by
less
intraindividual
variations.
The
pharmacokinetics
parameters
(Table
I)
show
that
the
mean
time
to
peak
plasma
level
for
Indian
J
Physiol
Pharmacol
1990;
34(3)
TABLE
I:
Pharrnacokintic
parameters
for
griseofulvin
after
administration
of
either
microsized
or
ultra-microsized
tablets
in
non
-fasting
volunteers.
Parameter
Unit
Microsized
tablets
mean±SEM
Ultra-microsized
t
-test
tablets
mean±SEM
1/2
hr
20.88±2.55
AUC
0-732
pg
html
I
4.14±
2.33
t
max
hr
2.515±0.33
Cp
max
µg/m1
.6815±0.10
13.90±2.03
16.25±1.16
2.440±0.54
.8043±0.079
p<0.1
N.S.
N.S.
N.S.
ultramicrosize
and
microsize
tablets
are
comparable.
However
the
maximum
plasma
level
and
AUC
(0
—>
32)µg
h/ml
are
slightly
higher
for
ultramicrosize
preparations.
The
plasma
half
life
of
griseofulvin
is
smaller
for
the
ultramicrosize
preparations.
DISCUSSION
The
bioavbailability
of
griseofulvin
(as
indicated
from
its
AUC)
after
its
administration
to
fasting
volunteers,
is
reported
to
be'
much
higher
for
ultramicrosize
tablets
compared
to
microsized
tablets
(9,
10).
Similarly,
ultramicrosize
tablets
produce
much
higher
peak
plasma
level
(0.
79-0.86
µg/ml,
compared
to
0.52-0.58
µg/m1
for
microsized
tablets)
and
peak
level
will
be
reached
much
faster
(3.3-3.8
hr
compared
to
9.1-9.2
hr
for
microsize
preparations).
In
contrast
to
results
in
fasting
volunteers,
our
results
show
that
when
griseofulvin
was
administered
with
a
fatty
meal
in
this
study
the
difference
between
ultramicrosize
and
microsize
preparations
was
not
significant
and
both
preparations
are
absorbed
to
the
same
extent
and
with
same
rates,
comparable
to
those
following
administration
of
ultramicrosized
tablet
to
fasting
volunteers.
Therefore
it
can
be
concluded
that
administration
of
griseofulvin
preparations
with
a
fatty
meal
will
tend
to
reduce
the
differences
between
various
preparations.
This
may
have
resulted
from
the
dissolution
of
griseofulvin
in
lipids
inside
GI
lumen.
It
has
been
previously
shown
that
the
bioabailability
of
griseofulvin
is
markedly
enhanced
by
concomintent
inagestion
of
food
and
milk
(11).
However,
the
intraindividual
variation
is
much
Indian
I
Physioi
Pharmacol
1990;
34(3)
Bioavailability
in
Nonfasting
Volunteeis
159
GRIS
(dp)
o.
1
L
1
Time(h)
Fig.
1:
Individual
plasma
concentration
of
griseofulvin
after
administration
of
two
125
mg
micrusized
griseofulvin
tablets
(Gris
dp)
to
6
healthy
and
non
-fasting
volunteers.
The
letters
refer
to
individual
volunteers.
32
160
Bijanzadeh
et
al
Indian
I
Physiol
Pharrnacol
1990;
34(3)
1.0
A
043
GRIS—PEG(Wander)
0.6
E
0.4
0
0.2
2
1
4
3
'
2
Time(h)
Fig.
2:
Individual
plasma
concentration
of
griseofulvin
after
administration
of
two
125
mg
ultra
-micronized
griseofulvin
tablets
(GRIS-PEG)
to
6
healthy
and
non
-fasting
volunteers.
The
letters
refer
to
same
individual
volunteers
as
in
Fig.
1.
Indian
J
Physic)!
Pharmacol
1990;
34(3)
less
for
the
ultramicrosize
tablets
and
its
apparent
t
112
is
lower
compared
to
microsized
tablets
(Figs.
1
&
2
and
table
II).
Since
apperant
t
1/2
of
griseofulvin
is
dependent
on
its
rate
of
absorption
(9)
the
lower
t
1/2
for
ultramicrosized
tablets
is
indicative
of
faster
rate
of
absorption
for
this
preparation.
Bioavailability
in
Nonfasting
Volunteers
161
In
conclusion,
this
study
shows
that
coadministration
of
griseofulvin
with
food
tend
to
minimize
the
difference
between
various
preparations,
but
the
griseofulvin
absorption
from
ultramicrosized
tablets
still
is
more
reliable
and
uniform.
Therefore,
while
ultramicrosized
formulation
does
not
justify
a
reduced
dosage,
is
still
preferable
preparation.
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