Pentamidine: Clinical pharmacologic correlations in man and mice


Waalkes, T.P.; Denham, C.; DeVita, V.T.

Clinical Pharmacology and Therapeutics 11(4): 505-512

1970


Patients with malignant disease complicated by diffuse interstitial pneumonia due to proved or suspected Pneumocystis carinii were given pentamidine in the dosage schedule recommended for this infection. By means of a sensitive method of assay, the plasma levels and urinary excretion of pentamidine during therapy were studied in these patients. Following the intramuscular administration of pentamidine, plasma levels were low and urinary excretion prolonged. After a single intraperitoneal injection in mice, the tissue distribution levels and excretion pattern for pentamidine were determined at various time intervals. There was storage of the drug in tissues and excretion was delayed. The highest concentration of pentamidine was found in the kidney. In mice pentamidine is eliminated primarily intact with little, if any, altered. The available data in man also suggested that pentamidine is retained, bound to tissues, and excreted over an extended period. Although renal abnormalities followed pentamidine, it was not possible to implicate the drug in all cases because of the seriousness of the illness and the concomitant use of other drugs. Pentamidine is useful in preventing disease due to Trypanosoma gambiense as well as effective in the treatment of diffuse interstitial pneumonia due to Pneumocystis carinii. The frequency of this type of pneumonia in cancer patients and in patients undergoing organ transplantation suggests the need for studies in animals and man.

Pentamidine:
Clinical
pharmacologic
correlations
in
man
and
mice
Patients
with
malignant
disease
complicated
by
diffuse
interstitial
pneumonia
due
to
proved
or
suspected
Pneumocystis
carinii
were
given
pentamidine
in
the
dosage
schedule
recommended
for
this
infection.
By
means
of
a
sensitive
method
of
assay,
the
plasma
levels
and
urinary
excretion
of
pentamidine
during
therapy
were
studied
in
these
patients.
Following
the
intramuscular
administration
of
pentamidine,
plasma
levels
were
low
and
urinary
excretion
prolonged.
After
a
single
intraperitoneal
injection
in
mice,
the
tissue
distribution
levels
and
excretion
pattern
for
pentamidine
were
determined
at
various
time
intervals.
There
was
storage
of
the
drug
in
tissues
and
excretion
was
delayed.
The
highest
concentration
of
pentamidine
was
found
in
the
kidney.
In
mice
pentamidine
is
eliminated
primarily
intact
with
little,
if
any,
altered.
The
available
data
in
man
also
suggested
that
pentamidine
is
retained,
bound
to
tissues,
and
excreted
over
an
extended
period.
Although
renal
abnormalities
followed
pentamidine,
it
was
not
possible
to
implicate
the
drug
in
all
cases
because
of
the
seriousness
of
the
illness
and
the
concomitant
use
of
other
drugs.
Pentamidine
is
useful
in
preventing
disease
due
to
Trypanosoma
gambiense
as
well
as
effective
in
the
treatment
of
diffuse
interstitial
pneumonia
due
to
Pneumocystis
carinii.
The
frequency
of
this
type
of
pneumonia
in
cancer
patients
and
in
patients
undergoing
organ
transplantation
suggests
the
need
for
studies
in
animals
and
man.
T.
Phillip
Waalkes,
Ph.D.,
M.D.,
Charlene
Denham,
B.A.,
and
Vincent
T.
DeVita,
M.D.
Bethesda,
Md.
The
Human
Tumor
Cell
Biology
Branch
and
the
Solid
Tumor
Service,
Medicine
Branch,
National
Cancer
Institute,
National
Institutes
of
Health
Interest
in
pentamidine
(
4,4'-diamidino-
phenoxypentane)
has
been
stimulated
by
its
value
in
the
treatment
of
diffuse
inter-
stitial
pneumonia
caused
by
Pneumocystis
carinii.
2
'
9
In
40
per
cent
of
patients
with
malignant
disease
who
develop
diffuse
in-
terstitial
pneumonia
during
treatment
with
Received
for
publication
Feb.
6,
1970.
Accepted
for
publication
March
31,
1970.
immunosuppressive
drugs,
the
etiologic
agent
has
been
found
to
be
Pneumocystis
canna.'
It
is
also
a
frequent
complication
in
patients
undergoing
organ
transplan-
tation
who
receive
immunosuppressive
drugs.
18,
23
Renal
toxicity
due
to
pentami-
dine
has
only
recently
been
reported
and
needs
further
evaluation.
2,
3
In
the
past,
pharmacologic
studies
have
been
hampered
by
the
lack
of
sufficiently
sensitive
methods
505
506
Waalkes,
Denham,
and
DeVita
Clinical
Pharmacology
and
Therapeutics
of
assay
in
blood,
urine,
and
tissues.
A
procedure
has
now
been
devised
which
measures
the
fluorescence
of
the
end
prod-
uct
of
the
reaction
between
pentamidine,
glyoxal,
and
benzaldehyde,
permitting
the
assay
of
pentamidine
in
low
concentrations
in
biological
materials.
24
The
purpose
of
this
study
was
to
deter-
mine
the
plasma
and
urine
levels
and
the
urinary
excretion
of
pentamidine
following
intramuscular
injection
in
patients
under-
going
a
therapeutic
trial
with
the
drug.
To
complement
this
evaluation,
tissue
levels
and
excretion
in
mice
were
also
determined
at
various
time
intervals
after
the
injection
of
pentamidine.
Materials
and
methods
Patients.
Plasma
and
urine
were
obtained
from
7
patients
with
malignant
disease
re-
ceiving
pentamidine
for
proved
or
sus-
pected
Pneumocystis
carinii
pneumonia.
The
dose
and
schedule
of
administration
were
those
recommended
by
the
manufac-
turer,
a
single
injection
of
4
mg.
per
kilo-
gram
of
pentamidine
isethionate
intramus-
cularly
per
day.
The
duration
of
therapy
varied
depending
upon
the
patient's
status,
but
usually
was
maintained
for
10
to
12
days.
Blood
was
drawn
with
the
use
of
heparin
as
an
anticoagulant,
and
the
stud-
ies
were
performed
on
plasma.
Twenty-
four
hour
urine
collections
were
made,
re-
frigerated,
and
aliquot
samples
frozen
for
subsequent
analysis.
Mice.
Mice
were
injected
intraperito-
neally
with
10
mg.
per
kilogram
(
calcu-
lated
as
base)
of
pentamidine
isethionate.
The
animals
were
kept
in
individual
glass
metabolism
cages,
and
urine
was
collected
free
of
feces
by
use
of
an
attached
anal
cup.
16
A
few
drops
of
0.1N
HCI
were
added
to
the
urine
collection
tube
to
main-
tain
an
acid
pH.
Each
day
the
glass
cage
was
washed
with
water,
the
fi
nal
urine
vol-
ume
adjusted
to
15
ml.
per
24
hour
period,
and
frozen
for
subsequent
analysis.
The
feces
were
removed
from
the
anal
cup
cup
daily
and
frozen.
The
animals
were
killed
at
specified
intervals.
Organs,
tissues,
and
feces
were
weighed
and
homogenized
in
5
to
7
times
the
volume
of
0.1N
HCI.
Method.
The
procedure
of
Waalkes
and
DeVita
24
was
used
for
the
assay
of
pen-
tamidine.
By
this
method,
pentamidine
was
extracted
under
basic
conditions
from
plasma,
urine,
and
tissue
samples
into
or-
ganic
solvents.
After
this
extraction
and
the
subsequent
concentration
of
the
pen-
tamidine
into
acid,
the
reaction
between
pentamidine,
glyoxal,
and
benzaldehyde
to
form
a
fl
uorescent
end
product
was
carried
out
in
basic
medium
following,
in
general,
a
modification
of
the
procedure
for
aro-
matic
diamidines
developed
by
Jackson
and
associates.
4
°
After
extraction
of
this
product
into
organic
solvents,
the
fi
nal
de-
termination
was
made
utilizing
an
Aminco-
Bowman
spectrophotofluorometer.
The
specificity
of
the
reaction
between
aromatic
amidines,
glyoxal,
and
benzalde-
hyde
as
assayed
by
Jackson
and
associatesl°
has
been
thoroughly
investigated
by
these
authors.
Aliphatic
amidines
and
a
large
variety
of
compounds
present
in
biological
fl
uids
which
might
give
a
false
positive
re-
sult
were
tested.
Either
these
materials
did
not
react
with
the
reagents
or
the
products
of
the
reaction
were
not
fl
uorescent.
The
possibility
that
metabolic
breakdown
products
of
pentamidine
containing
an
aro-
matic
structure
might
give
an
erroneous
impression
of
the
amount
of
intact
pen-
tamidine
present
in
biological
materials
was
considered.
Previously,
Launoy
and
associates,
13,
14
using
two
different
samples
of
pentamidine-C
44
,
one
with
the
radioac-
tive
carbon
in
the
central
straight
chain
pentane
structure,
the other
with
it
as
a
terminal
carbon,
studied
the
deposition
and
metabolism
of
pentamidine
in
mice
and
rats.
Pentamidine
was
found
to
be
excreted
intact
in
urine
and
feces
with
no
evidence
of
any
breakdown
products.
Studies
with
the
use
of
thin
-layer
chromatography
24
are
in
agreement
with
this
fi
nding.
Duplicate
samples
were
analyzed
in
all
cases.
Samples
of
plasma,
urine,
or
tissues,
identical
samples
with
known
amounts
of
pentamidine
added
to
determine
recovery,
Volume
11
Number
4
Pentamidine
507
standard
pentamidine
solutions
alone,
and
a
reagent
blank
were
always
run
through
the
entire
procedure.
Results
A
summary
of
the
plasma
pentamidine
levels
with
time
following
the
daily
intra-
muscular
administration
of
the
drug
to
pa-
tients
is
presented
in
Table
I.
The
plasma
levels
were
low,
did
not
rise
appreciably
immediately
after
the
injection,
remained
essentially
the
same
throughout
the
24
hour
period,
and
did
not
increase
with
succeed-
ing
days
of
treatment.
If
a
rise
in
plasma
level
was
noted,
the
usual
time
was
at
one
hour
after
the
injection.
The
highest
levels
were
found
in
patients
with
an
elevated
blood
urea
nitrogen
(BUN).
Urine
levels,
24
hour
urine
excretion,
and
one
-hour
plasma
levels
of
pentamidine
with
corresponding
changes
in
BUN
in
the
patients
are
shown
in
Table
II.
The
evaluation
of
the
effect
of
pentami-
dine
on
renal
function
is
complicated
in
this
study
by
the
fact
that
3
of
the
5
pa-
tients
who
had
elevations
in
BUN
levels
were
receiving
antibiotics
capable
of
pro-
ducing
renal
toxicity.
A
detailed
case
sum-
mary,
however,
of
a
patient
with
relatively
severe
abnormal
renal
function
while
re-
ceiving
only
pentamidine
has
been
pre-
viously
reported.
3
In
addition,
those
pa-
tients
who
had
elevated
BUN
levels
prior
to
pentamidine
therapy
(Patients
A,
B,
C,
and
E)
were
seriously
ill
with
diffuse
inter-
stitial
pneumonia.
Patient
C
had
severe
re
-
Table
I.
Summary
of
plasma
pentamidine
levels
with
time
after
the
daily
intramuscular
injection
of
4
mg.
per
kilogram
of
the
isethionate
to
patients
Values
(µg./ml.)
Time
Number
(hours)
Average
I
Range
analyzed
1/2
0.4
0.3-0.5
11
1
0.5
0.3
-
1.4
20
3
0.3
0.2-0A
11
6
0.3
0.2-03
6
24
0.3
0.2
-
0.4
14
nal
failure
associated
with
a
rapidly
pro-
gressing
malignancy
and
expired
secondary
to
pneumonia.
The
terminal
increasing
azo-
temia
was
considered
unrelated
to
pentam-
idine
therapy.
The
BUN
levels
for
Patients
A
and
E
were
moderately
elevated
prior
to
pentamidine
injections,
increased
during
treatment,
and
returned
to
normal
range
following
therapy.
These
increases
in
BUN
could
also
have
resulted
from
the
other
therapies.
Patient
B,
who
was
not
receiv-
ing
nephrotoxic
antibiotics
at
the
onset
of
pentamidine
therapy,
had
a
mildly
elevated
BUN
level
before
pentamidine
treatment
but
a
marked
rise
during
therapy,
with
a
subsequent
return
to
normal.
Of
those
patients
showing
a
rise
in
BUN
level
during
treatment,
Patient
D
was
the
only
one
in
whom
the
BUN
was
normal
before
pentamidine.
For
Patient
D
the
rise
in
BUN
during
therapy
was
moderate
with
an
ultimate
return
to
normal
values.
This
patient
did
not
receive
ne-
phrotic
drugs
just
before
or
in
conjunction
with
pentamidine.
For
those
patients
with
an
increase,
the
peak
elevation
of
the
BUN
was
between
8
and
14
days
after
onset
of
pentamidine
treatment
with
return
to
normal
between
Days
17
and
30.
In
Pa-
tients
A,
B,
and
E,
an
increase
in
serum
creatinine
and
a
decrease
in
creatinine
clearance
were
found
and
paralleled
the
changes
in
BUN
values.
Although
minor
changes
in
liver
enzymes
and
alkaline
phosphatase
were
noted
in
some
of
the
patients,
there
were
erratic
and
difficult
to
relate
to
pentamidine
treat-
ment.
Except
for
one
patient
(F),
who
had
a
fasting
blood
sugar
of
76
before
treatment
and
57
mg.
per
cent
on
Day
9,
no
significant
changes
were
noted
in
the
blood
sugar,
serum
calcium,
or
potassium
levels.
The
amount
of
pentamidine
in
the
urine
for
each
6
hour
period
of
a
day
was
deter-
mined.
For
5
patients,
of
the
total
excreted
during
the
24
hours
after
the
injection
of
pentamidine,
one
half
to
two
thirds
oc-
curred
during
the
fi
rst
6
hours
after
ad-
ministration
of
the
drug.
After
cessation
of
Table
II.
Urine
and
plasma
levels
and
urine
excretion
of
pentamidine
with
BUN
changes
in
patients
during
treatment
with
pentamidine
isethionate
4
mg.
per
kilogram
per
day
given
intramuscularly
Patient
(age)
Diagnosis
Days
of
pentamidine
therapy
BUN
(level/day
from
onset
of
treatment)
Plasma
level*
Urine
level*
(24
hour)
Other
drugs
used
during
pentamidine
treatment
Before
Peak
Return
to
normal
Day
(onset
of
treatment)
lig/ml.f
Day
(onset
of
treatment)
,ug/ml.f
mg.
Daily
dose
(%)
A
Chronic
5
28/1
102/11
16/24
1
0.3
Kanamycin
(43)
granulocytic
2
0.3
Cephalothin
leukemia
3
0.8
Colistimethate
(
acute
phase)
5
1.4
B
Chronic
12
25/0
75/13
19/24
3
0.3
3
21
21
15
Cephalothin
(
58
)
granulocytic
6
0.3
4
25
26
18
Prednisone
leukemia
5
33
30
21
Allopurinol
(
acute
phase)
6
31
21
15
Isoniazid
7
29
26
18
8
31
41
29
9
29
26
18
10
24
24
17
11
25
24
17
13
20
19
Acute
2
40/0
Continued
to
rise
1
0.8
2
20
20
15
Cephalothin
(44)
C
myelogenous
to
day
of
death
2
1.0
3
15
10
Ampicillin
leukemia
3
0.6
Colistimethate
Reticulum
10
15/1
34/14
14/30
3
0.6
6
25
23
16
None
(44)
D
cell
6
0.4
8
25
25
17
sarcoma
7
0.4
8
0.5
10
0.5
E
Lympho-
5
48/0
87/8
19/17
1
0.4
2
12
10
11
Cephalothin
(
53
)
sarcoma
3
0.6
3
29
27
21
Tetracycline
5
25
20
14
Methicillin
Isoniazid
F
Acute
lym-
10
Normal
throughout
3
0.4
3
12
10
14
Ampicillin
(
10)
phatic
leukemia
8
0.3
8
12
12
17
C
Acute
lym-
11
Normal
throughout
3
0.4
3
10
8
14
Ampicillin
(
8
)
phatic
leukemia
9
0.3
9
10
10
17
Polymyxna
5-Fluorocytidine
Cloxacillin
Steroids
*One
hour
after
injection
of
pentamidine.
{Expressed
as
pentamidine
base.
0
CO
Waalkes,
Denham,
and
DeVita
I
2
Volume
11
Number
4
Pentamidine
509
therapy,
the
duration
of
the
excretion
of
pentamidine
in
urine
was
determined
in
3
patients
at
intervals
of
1
to
2
weeks
(not
shown).
Decreasing
amounts
of
pentami-
dine
were
present
up
to
6
to
8
weeks
after
termination
of
the
drug
treatment
but
none
thereafter.
The
levels
of
pentamidine
found
in
var-
Table
III.
Distribution
and
level
of
pentamidine
in
various
mouse
organs
at
24
and
72
hours
after
10
mg.
per
kilogram
of
pentamidine
intraperitoneally
Organ
µg/Gm.
in
tissue
24
hr.
I
72
hr.
Kidney
52
20
Liver
28
10
Spleen
11
3
Remainder
of
abdominal
and
pelvic
organs
8
2
Lung
5
4
Remainder
of
carcass
3
2
Brain
<0.3+
<0.2
*Expressed
as
pentamidine
base.
Average
value
given
from
two
animals
at
each
time.
+The
symbol
(
<)
means
a
small
fluorescence
reading
was
obtained
but
no
fluorescence
peak
or
curve
charac-
teristic
for
pentamidine.
ious
mouse
organs
24
and
72
hours
after
the
single
intraperitoneal
dose
of
10
mg.
per
kilogram
of
pentamidine
are
shown
in
Table
III.
At
both
times,
the
greatest
con-
centration
of
the
drug
per
gram
of
tissue
was
found
in
the
kidney,
with
the
liver
next.
The
remaining
organs
tested
had
a
significantly
smaller
quantity
found
per
gram
of
tissue.
The
level
of
pentamidine
in
the
kidney,
liver,
and
the
remainder
of
the
carcass
of
mice
was
determined
at
intervals
over
a
25
day
period.
The
results
(
Table
IV)
show
pentamidine
in
signifi-
cant
concentrations
in
tissues
over
this
period
of
time,
suggesting
that
the
com-
pound
is
bound
to
tissues
and
slowly
re-
leased.
The
excretion
of
pentamidine
for
mice
was
studied
over
a
90
hour
period
after
a
single
intraperitoneal
injection
of
pentam-
idine
(
Table
V).
The
amount
in
the
urine,
feces,
and
remainder
of
the
carcass
was
determined
at
various
time
intervals.
Pentamidine
is
eliminated
by
way
of
both
the
urinary
system
and
gastrointestinal
tract,
the
former
being
the
main
route.
Variable
but
generally
small amounts
of
the
drug
were
recovered
in
the
urine
of
mice
up
to
90
hours.
Most
of
the
remaining
drug
could
be
accounted
for
as
intact
pen-
tamidine
bound
to
tissue.
Table
IV.
Amount
of
pentamidine
in
mouse
organs
and
tissues
at
intervals
after
the
injection
of
pentamidine
isethionate
10
mg.
per
kilogram
intraperitoneally
Time
after
administration
(days)
Dose
given
(mg.)
,ug/Gm.
in
tissues
Total
pentamidine
in
tissues
Kidney
Liver
Remainder
of
carcass
mg.
1
%
Dose
1
0.25
52
28
4
0.15
60
3
0.28
20
10
2
0.07
25
4
0.25
12
6
2
0.05
20
6
0.24
13
5
2
0.05
21
8
0.26
13
4
2
0.05
19
15
0.27
10
2
1
0.04
15
25
0.26
5
0.3
<0.4+
0.01
4
°Expressed
as
pentamidine
base.
Average
of
2
animals
for
each
time
period.
}Symbol
(
<
)
indicates
a
reading
but
no
characteristic
fluorescence
peak
or
curve
for
pentamidine.
510
Waalkes,
Denham,
and
DeVita
Clinical
Pharmacology
and
Therapeutics
Table
V.
Excretion
of
pentamidine
°
and
recovery
following
the
intraperitoneal
injection
of
10
mg.
per
kilogram
of
the
drug
into
mice
Mouse
Amount
of
pentamidine
injected
(mg.)
%
Total
dose
recovered
Distribution
Carcass
Urine
Feces
No.
Time
sacrificed
(hours)
mg.
(
pg/Gm.)
%
Total
recovered
mg.
%
Total
recovered
mg.
%
Total
recovered
1
0.26
110
0.28
100
1
(11)
2
0.26
100
0.26
100
(10)
3
0.27
104
0.20
72
0.06
21
0.02
7
18
(7.5)
4
0.27
100
0.19
72
0.07
25
0.01
3
(7.2)
5
0.25
104
0.15
58
0.09
34
0.02
8
41
(6.3)
6
0.26
100
0.17
65
0.07
27
0.02
8
(6.5)
7
0.29
86
0.10
40
0.12
48
0.03
12
90
(3.7)
8
0.27
88
0.11
46
0.09
37
0.04
17
(4.3)
*Expressed
as
free
base.
Discussion
At
present,
pentamidine
is
regarded
as
the
agent
of
choice
in
the
treatment
of
early
African
sleeping
sickness,
15
prophy-
laxis
against
Trypanosoma
gambiense,
15
and
diffuse
interstitial
pneumonia
due
to
Pneumocystis
carinii.
2,
5
'
19
Considerable
experience
has
been
gained
in
patients
with
the
injection
of
pentamidine
by
either
the
intravenous
or
intramuscular
routes.
Because
of
the
high
incidence
of
immedi-
ate
undesirable
effects
when
given
intra-
venously,
the
intramuscular
route
is
pre-
ferred.
The
most
common
metabolic
effect
reported
has
been
on
blood
glucose
lev-
e
j
s.
i,
6,
11,
12,
21,
22
Payet
and
Sankale
47
re-
ported
on
4
patients
with
trypanosomiasis
in
whom
azotemia
developed
during
ther-
apy
with
pentamidine
and
persisted
for
2
to
3
weeks.
In
rabbits
at
doses
of
40
mg.
per
kilogram,
diamidines
have
been
re-
ported
to
cause
a
transient
azotemia,
25
and
in
guinea
pigs
to
have
produced
fatty
de-
generation
of
the
liver
and
cloudy
swelling
of
the
kidney.
20,
25
Wien
and
associates
25
reviewed
the
metabolic
effects
in
animals
produced
by
certain
aromatic
diamidines
including
pentamidine.
These
authors
found
that
doses
producing
no
apparent
effects
on
blood
sugar
in
rabbits
caused
a
signifi-
cant
rise
in blood
urea
and
nonprotein
nitrogen.
This
was
particularly
true
for
4,4'-diamidinophenoxypropane
but
also
with
pentamidine
itself.
At
toxic
levels,
fatty
degeneration
of
the
liver
was
found,
and
in
rabbits
and
dogs
a
fall
in
serum
calcium
and
potassium
levels.
Previous
work
by
French
and
Milne
4
with
cattle
and
sheep
indicated
pentamidine
given
in
tolerated
doses
produced
kidney
dysfunc-
tion
prior
to
any
evidence
of
liver
damage.
Launoy
and
associates,
43
using
pentam-
idine-C
44
,
studied
the
storage
and
ex-
cretion
of
the
compound
in
mice
over
a
Volume
11
Number
4
Pentamidine
511
period
of
5
days.
They
concluded
that
pentamidine
was
excreted
primarily
in
the
urine
as
such.
The
radioactivity
remaining
in
tissues
was
greatest
in
the
kidney
and
liver
after
the
5
days.
No
radioactivity
was
noted
in
the
blood.
There
were
similar
fi
ndings
in
rats.
14
The
results
of
the
experiments
carried
out
in
the
present
study
are
in
essential
agreement
with
those
of
Launoy
and
asso-
ciates.
11
After
intraperitoneal
injections
in
mice,
the
highest
concentration
of
pentam-
idine
was
in
the
kidney
and
then
the
liver.
Excretion
of
the
drug
was
primarily
by
the
kidneys.
The
quantitative
estima-
tion
of
the
amounts
excreted
and
retained
in
tissues
over
a
period
of
several
days
after
a
single
injection
suggests
that
pen-
tamidine
is
not
metabolized
to
any
signifi-
cant
extent
but
is
bound
in
tissues
with
gradual
release.
The
nature
of
this
binding
is
obscure.
In
patients
treated
with
pentam-
idine,
the
fi
ndings
suggest
a
similar
pro-
longed
storage
and
slow
release.
Tissue
levels
and
excretion
of
pentam-
idine
following
repeated
injections
in
mice
were
not
studied.
Prior
work
by
Hamptons
with
stilbamidine
suggested
a
peak
tissue
saturation
level
for
this
aro-
matic
amidine
after
repeated
administra-
tion
of
the
drug
to
rats.
With
small
daily
injections
of
stilbamidine
(
1
and
2
mg.
per
kilogram),
no
detectable
amount
was
found
in
the
urine
after
several
days.
With
larger
daily
injections
(
5
and
10
mg.
per
kilogram),
the
quantity
excreted
at
fi
rst
was
low
but
similar
in
amount
from
day
to
day
until
after
about
10
injections
when
a
sudden
rise
occurred.
The
level
remained
high
thereafter.
Presumably,
a
comparable
situation
might
occur
with
pentamidine.
For
the
patients
studied,
the
blood
levels
during
therapy
remained
low
and
the
amount
excreted
in
the
urine
was
approxi-
mately
20
per
cent
or
less
of
the
daily
dose.
Under
these
conditions,
with
continued
daily
therapy
one
could
speculate
that
cumulative
toxic
effects
on
tissues,
par-
ticularly
renal
and
hepatic,
might
be
noted
depending
on
the
amount
of
the
compound
excreted
in
the
feces,
or
possibly
metabo-
lized,
and
the
functional
capacity
of
these
organs.
In
the
doses
used
for
prophylaxis
against
trypanosomiasis,
essentially
no
toxicity
has
been
noted;
the
effectiveness
of
intermit-
tent
phophylaxis
in
this
disease
suggests
that
the
compound
is
stored
for
long
periods
of
time
in
normal
organs
and
tis-
sues.
For
patients
seriously
ill
with
a
malig-
nancy
complicated
with
a
diffuse
interstitial
pneumonia,
pentamidine
in
the
doses
used
can
cause
a
rise
in
the
BUN,
suggesting
dis-
tinct
renal
toxicity.
With
recovery
from
the
pneumonia
and
cessation
of
pentamidine
therapy,
the
BUN
gradually
returns
to
nor-
mal
values.
Renal
transplant
patients
are
prime
candidates
for
the
development
of
Pneumocystis
carinii
pneumonia;
the
bind-
ing
of
this
drug
to
renal
tissues
may
cause
difficulty
with
already
compromised
renal
functions.
Although
no
evidence
is
present-
ly
available
to
support
the
use
of
prophy-
lactic
treatment
with
pentamidine
in
pa-
tients
undergoing
immunosuppression,
the
available
pharmacologic
and
clinical
evi-
dence
for
binding
of
the
intact
drug
to
tissues
suggests
the
need
of
investigation
in
animals
and
in
man.
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