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Pharmacokinetics of Phenformin in Man

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

was reAt that

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

the dose administered


to sub2, respectively.
This
is conpublished
findings.2
Most
of

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

and for plasma


of phenformin

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