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DAVID
ALKALAY.
MS..
fate
of biguanides
viewed
by Beckmann
time,
specific
cedures
and
for
were
still
sensitive
in
unavailable.
with
and
the
from
nine
test
half-life
composite
half-life
hours,
the
of
and
one
of
phenformin
in
a 2:1
cent
excreted
subject,
the
and
its
was
reported
urine
a)
a)
I.-
30
methods
for
of biguanides
new
the
specific
in biologic
-a
.-
Subject
C.)
x
w
a)
U)
10
0
0
12
Days Following
Fig.
in
1.
Cumulative
urine,
excretion
following
25-mg
DBI
oral
tablets
of
to
each
to occur
and
sensitive
determination
fluids
came
oral
disease.
dose
tablets)*
into
four
They
received
of phenformin
after
an
plasma,
days,
overnight
sputum,
phar-
in Fig.
amounts
excreted
obtain
physical
results
history
or
446
fragmentog-
methodology
information
phenformin
The two
enabled
about
the
examination
and laboratory
test
were within
normal
limits,
had no
of peptic
ulcer,
drug
dependence
abuse,
From
the
Division,
mass
or
Research
Ciba-Geigy
cardiovascular,
renal,
Department,
Corporation,
Pharmaceutical
Ardsley,
or
sayed
*Geigy
N.Y.
Geigy
25-mg
DBI
fast.
and
For
urine
were
collected
at
predetimes,
and the samples
were
asfor
phenformin.
1. The
in the
per cent of
jects
1 and
sistent
with
the
first
a 100-mg
(four
in two adult
subjects,
whose
to
macokinetics
of
male
volunteers.
four
human
p-phenohic
urinary
drug
two
volunteers
us
two
subjects.
excretion
Cumulative
data
for the
new
of
of
chromatography
This
phenformin
administration
specimens
termined
raphy.34
Drug Administration
use. They
are based
on conversion
of the
biguanides
into
substituted
S-triazines,
which
are
assayable
by means
of gas
or
No.1
20
hepatic
recently,
No.2
of
in the
ratio.
More
and
N.J.
3.2
24-hour
period
followof a 50-mg
oral dose.
additional
metabolite
in
the
was
Subject
drug
and
this basis,
54 per
drug
were
for
averaged
approximately
administered
urine
during
ing administration
In
excretion
subjects,
data
rates
urinary
excretion
of unchanged
the p-phenolic
metabolite.2
On
the
in a
JR.. M.D.,
and Summit,
40
fluids
Consequently,
study
bioavailability
generated
pro-
biologic
E. WAGNER.
Ardsley, N.Y.,
50
assaying
biguanides
phenformin
KHEMANI.
B.A.. WILLIAM
M. FRED BARTLETT.
Ph.D.
in man
in 1968.1
HE
LAKSHMI
excretion
plotted
of unchanged
urine
represent
drug
29 and
41
drug
elimination
24 hours
following
Pharmaceuticals,
Corporation.
The
are
Inc.,
Ardsley,
Journal
occurs
dose
of
during
the
administra-
Division
of
N.Y.
Clinical
Pharmacology
Ciba-
PHARMACOKINETICS
tion,
not
but excretion
insignificant.
drug
excretion
not
less than
phenformin
are
in subsequent
Consequently,
the
for
Fig.
2.
urinary
excretion
and saliva
are presented
The
terminal
clines
in all curves
life
of approximately
untreated
indicate
11
diabetic
following
dose.5
It
half-life
longer
of
previous
estimates.2
tion
profiles
depicted
requires
of
appears,
hours
the
in
the
drug
24 hours
the
equilibrium
formin-C
used
these
In
to
plasma
In
excrethe /-
amounted
Previously
to 18.70.7
reported
from
significant6
day
before
Subject
be-
concentration
about
130
not
No.1
Subject
to deof
could
ac-
phenformin
at
pro37#{176}Cby
method.
human
were
for
which
in the
ng/ml.
Drug
per
values
to
Phen-
plasma
determinations,
the drug
kept
at
en-
order
binding
assessed
fresh
saliva
those
which
findings,
conby
one
reported
proteins
dialysis
five
much
explain
in
plasma.
is
about
very
may
than
phenformin
than
suggested
the urinary
in Fig.
2,
be
part,
lower
was
and
in
during
administra-
half-life
extent
for
therefore,
the
to
binding
single
drug
concentrations
tein
by
of
after
considerably
termine
estimates
excretion
estimated
count
10 and
urinary
therefore
This,
in
countered
halfhalf-
was
indicated
in the plasma
at
24
short
are
de-
a drug
hours.
A
administration
therapeutic
phase
first
Half-life
on
previously.2
Phenformin
concentrations
graphically
exponential
life
of about
9 hours
phenformin
levels
seen
that
the
siderably
only
tion
would
understated.
rates
MAN
apparent.
based
the
profiles
IN
coming
is
should
be monitored
for
three
to four
days
when
bioavaiiability
assessments
an
days
urinary
PHENFORMIN
attempted.
The
in
OF
plasma
was
binding
cent
have
12 and
(S.E.).
ranged
20
per
No.2
5,000
a:
a:
a,
0)
2,000
1,000
500
0)
C
E
a)
0)
0)
200
100
50
C
C
C
8)
U
C
0
0
20
Hours
Fig.
2. Time
concentrations
DBI
tablets
(rg/hr);
concentration
May-June,
1975
(S
Following
40
60
Drug
80
Administration
100
Hours
20
Following
Drug
Administration
profiles
for urinary
excretion
rates and for plasma
and saliva
of phenformin,
following
oral administration
of four
25-mg
to each
of
two
human
subjects:
(.
#{149})urinary
excretion
#{149})plasma
concentration
(ny/ml);
(*
#{163}) saliva
(-a gig).
447
ALKALAY,
cent.7
Protein
binding,
a major
factor
nounced
difference
tration
KHEMANI,
apparently,
in accounting
the
and
pro-
3.
concen-
saliva.
Summary
Phenformin
plasma,
was
and
from
two
four-day
tration
excreted
formin
third
unchanged
proffles
were
rates
and
concentrations.
declines
indicate
mately
11 hours.
19 per
cent
oral
of
in the
obtained
for
The
the
At
Ap-
drug
was
5.
Phenurinary
and
terminal
a half-life
of added
dose.
urine.
for
plasma
4.
the
adminis-
therapeutic
one
excretion
during
following
a single
urine,
obtained
volunteers
period
proximately
in
specimens,
healthy
of
assayed
sputum
6.
saliva
exponential
of approxi-
37#{176}C,plasma
bound
7.
phenformin.
References
1.
Beckmann,
man.
(1968).
2.
R.:
Ann.
Beckmann,
biologischen
448
The
New
H.:
lJber
Abbau
fate
Fork
die
of
Acad.
biguanides
in
Sci.
148:820
Resorption
von
und
1- (-Phenhthyl)
AND
biguanid
is not
for
in phenformin
in plasma
WAGNER,
den
-
BARTLETT
(Phenformin).
Diabetotogia
3:
368
(1967).
Matin,
S. B., Karam,
J., and Forsham,
P. H.:
A simple
ga.s-chromatographic
method
for
the
quantitative
estimation
of
the
hypoglycemic
biguanides
in biological
fluids
using
an electron
capture
detector.
Paper
presented
at the
15th
National
Meeting
of
the
APhA
Academy
of
Pharmaceutical
Sciences,
San
Diego,
California,
November
13, 1973.
Alkalay,
D., Volk,
J.,
and
Bartlett,
M. F.:
Conversion
of
biguanides
into
S-triazines
assayable
by gas
chromatography
or mass
fragmentography.
To be published.
Karam,
J., Matin,
S., Levin,
S., and Forsham,
P. II.:
Circulating
phenformin
(Pf)
levels:
implications
as to Pfs
therapeutic
action.
Diabetes
23 (Suppi.
1) :375
(1974)
(Abstr.)
Shepherd,
H. G., Jr.,
and
McDonald,
H. J.:
Binding
affinity
of
purified
plasma
proteins
for phenethylbiguanide,
an oral
hypoglycemic
compound.
Clin.
Chem.
4:496
(1958).
Garrett,
E.
R.,
Tsau,
J., and Hinderling,
P. H.:
Application
of ion-pair
methods
to
drug
extraction
from
biological
fluids.
fl:
Quantitative
determination
of
biguanides
in biological
fluids
and
comparison
of protein
binding
estimates.
J. Pharm.
Sci.
61:
1411
(1972).
Requests
for
reprints
should
be
addressed
David
Alkalay,
Ciba-Geigy
Corporation,
Mill
River
Road,
Ardsley,
N.Y.
10502.
The
Journal
of
Clinical
Pharmacology
to:
Saw