Nitrofurantoin disposition

Nitrofurantoin (50 mg) was administered in a three-way random crossover design to six healthy
men. After a 45-mM intravenous infusion the plasma concentration data could be described by a
two-compartment open-body model with a terminal 0/2 of 58.1 ± 15 mm. Oral availability of a
tablet was 0.87 ± 0.13 on a fasting stomach and 0.94 ± 0.13 when taken with food. Although
absorption appeared to be complete, the absorption rate profile was complex and erratic. Two
subjects failed to achieve the minimum effective urine concentration of 32 Aglml. After the
intravenous infusion 47 -± 13% of the dose was excreted unchanged in the urine and
1.2 0.3% was recovered as the reduced metabolite aminofurantoin.

Betty-ann Hoener, Ph.D., and Sean E. Patterson, Ph.D. San Francisco, Calif.
Department of Pharmacy, School of Pharmacy, University of California

Both the pharmacologic and toxicologic ef-
fects of nitrofurantoin appear to be caused by
binding of "activated" reduced metabolites to
deoxyribonucleic acid (DNA) or proteins.*
Therefore it is important to be able to charac-
terize the kinetic behavior of both nitrofurantoin
and its reduced metabolites. Most studies of ni-
trofurantoin disposition have been limited by
assays not sensitive enough to detect its plasma
levels.t Thus most studies of nitrofurantoin ki-
netics have measured urinary excretion rate or
unchanged nitrofurantoin in urine. Although
only 30% to 60% of the drug is excreted un-
changed in the urine, none of its metabolites
had been identified in humans. In the course of
Supported in part by Grant GM 27122 from the National Institutes
of Health and a Faculty Career Development Award to Betty-ann
Hoener from the University of California, San Francisco.
Received for publication Feb. 9, 1981.
Accepted for publication March 5, 1981.
Reprint requests to: Dr. Betty-Ann Hoener, Department of Phar-
macy, School of Phannacy, University of California, San Francisco,
CA 94143.
*References 7, 9, 21, 24, 34.
tReferences 1, 4, 12, 14, 16, 20, 22, 23, 25, 28-32, 35, 36, 38,
39, 41, 42.
808 0009-9236/81/060808+09$00.90/0 C) 1981 The C. V. Mosby Co.
in vitro studies on the reductive metabolism and
covalent binding of nitrofurantoin to DNA we
identified a reduced metabolite of nitrofuran-
toin, aminofurantoin.3 We had also developed
high-power liquid chromatographic (HPLC) as-
says for nitrofurantoin and metabolite in plasma
and urine .2' 17
Because it is recommended that nitrofuran-
toin be taken with food or milk, the effect of
food on the bioavailability of nitrofurantoin has
been a major concern. We therefore determined
the kinetics of distribution, metabolism, and
excretion of nitrofurantoin and its reduced me-
tabolite after doses intravenously, the rate and
extent of absorption of nitrofurantoin after
doses orally on a fasting stomach, and the effect
of food on the bioavailability of nitrofurantoin
after doses orally.
Methods
Our subjects were six healthy men ranging in
age from 25 to 35 yr, in weight from 62 to 80
kg, and in height from 177 to 183 cm. Their
serum creatinine levels ranged from 1 to 1.70
mg/dl. Each received 50 mg nitrofurantoin
Volume 29 809
Nitrofurantoin disposition
Number 6

Table I. Kinetic parameters*

Ter-
Infusion minal
Vol- Dose time V1 V dsst a g (t1/2) C1,, C1,4
unteer Treatment (mg) (min) (1) (1) (min') (min') (min) (1/mm) (111nit) ff.§

1 Oral-fasting 50.0 0.21 0.45

Oral-food 50.0 0.39 0.23
IV infusion 45.0 47.0 13.0 27.3 0.071 0.012 56.4 0.62 0.18 0.29
2 Oral-fasting 50.0 0.21 0.24
Oral-food 50.0 0.28 0.39
IV infusion 43.9 48.0 21.6 39.9 0.057 0.010 71.5 0.74 0.45 0.61
3 Oral-fasting 50.0 0.17 0.43
Oral-food 50.0 0.21 0.38
IV infusion 43.9 48.4 4.0 35.3 0.763 0.019 37.2 0.65 0.39 0.60
4 Oral-fasting 50.0 0.26 0.22
Oral-food 50.0 0.26 0.33
IV infusion 50.3 56.0 8.8 40.6 0.26 0.015 47.7 0.67 0.33 0.50
5 Oral-fasting 50.0 0.23 0.39
Oral-food 50.0 0.23 0.38
IV infusion 43.9 47.6 10.5 49.3 0.32 0.012 57.7 0.67 0.28 0.42
6 Oral-fasting 50.0 0.30 0.31
Oral-food 50.0 0.27 0.35
IV infusion 46.1 48.0 23.9 49.4 0.08 0.009 78.0 0.77 0.29 0.37
_x Oral-fasting 0.23 0.34
(SD) (0.05) (0.10)
Oral food 0.27 0.34
(0.06) (0.06)
IV infusion 13.6 40.3 0.26 0.013 58.1 0.69 0.32 0.47
(7.7) (8.5) (0.27) (0.004) (15.0) (0.06) (0.09) (0.13)
*IV infusion calculated by fitting to a two-compartment open-body model with zero-order infusion and first-order elimination weighed 1/Y,
r 0.986. AUC determined by log trapezoidal rule.
Dose AUMC T dose 5
(AUC)2 2 AUC.
AT,/AUC.
§A/dose.

under three conditions in a random crossover
design.
Study design. A solution (50 mg/150 ml) of
nitrofurantoin (Ivadantin) was freshly prepared
in 5% dextrose in water (Travenol). This solu-
tion was given by intravenous infusion over 45
min with a Harvard infusion pump. Blood
samples were drawn at 0, 10, 20, 30, 40, 45,
50, 60, 70, 90, 110, 130, 150, 180, 240, 300,
and 360 mm after the start of the infusion. Urine
was collected at 0, 45, 90, 120, 180, 240, 300,
360, 480, 600, and 1440 mm. A 50-mg tablet
(Furadantin) of nitrofurantoin was given with
240 ml water. Blood was drawn at 0, 10, 30,
45, 60, 75, 90, 120, 150, 180, 240, 300, 360,
420, and 480 mm. Urine was collected at 0, 30,
60, 120, 180, 240, 300, 360, 480, 600, and
1440 mm. A 50-mg tablet of nitrofurantoin was
given with 240 ml of water with a standardized
high-fat breakfast (900 calories, 30% fat).
Blood and urine samples were collected at the
same times as the fasting oral dose.
All subjects fasted after 10 P.M. on the night
before dosing. Because of potential interference
with the metabolite assay, no caffeinated prod-
ucts were allowed during the study. To ensure
adequate urination the subjects drank 240 ml
water before dosing, with the dose, and at 2, 4,
6, and 8 hr after taking the nitrofurantoin. A full
liquid lunch was consumed after the 240-min
sample. A 7-day washout period was included
between each dosing.
Analytic methods. A Waters Associates
Model ALC/GPC 244 with U6K universal in-
jector, dual-channel fixed-wavelength ultravio-
let absorption detector set at 280 and 365 nm,
810 Hoener and Patterson
120
Fig. 1. Semilog plot of the nitrofurantoin plasma concentrationstime. A 50-mg dose was given to
subjects 5(A) and 6(B) as a 45-min intravenous infusion (o- o), a tablet orally on a fasting stomach (0-0,
and a tablet orally with food (.-.).
and a dual-pen recorder (Houston) was used. A
30 x 3.9 mm (id) ,u-Bondapak C
column
(Waters) was used for the assay of nitrofuran-
toin. A 25 x 3.2 mm (id) LiChrosorb C
col-
umn (Altex) was used for the assay of amino-
furantoin. The chromatograph was operated
isocratically at a flow rate of 2 ml/min. Chart
speed was 15 cm/hr, and full-scale response
was 10 mV.
Nitrofurantoin and furazolidone (the internal
standard) were used as obtained (Norwich-Eaton
lots M8738 and S3071). Sterile nitrofurantoin
sodium (Ivadantin CN110397, expiration April
1981) and 50-mg nitrofurantoin tablets (Furan-
dantin, CNO3472, expiration October 1984)
were purchased from the University of Califor-
nia San Francisco inpatient pharmacy. The in-
travenous solution was assayed by HPLC to de-
termine the exact concentration. Nitrofurantoin
content of the tablets was verified by HPLC
using a modification of the United States Phar-
macopeia XX method." Glass-distilled metha-
nol was obtained from Burdick & Jackson.
Spectrophotometric grade dimethyl sulfoxide
and acetonitrile (Burdick & Jackson) were used
as received. 5-Nitro-2-furoic acid (the internal
standard; Aldrich) was used as received.
Clin. Pharmacol. Ther.
June 1981
600 120 240 360 480 600
mm
Aminofurantoin (1-((5-amino-2-furanyl)methy-
lene) amino-2,4-imidazolidenedione) was pre-
pared by catalytic hydrogenation of nitrofuran-
toin over 5% palladium on charcoal (ICN) and
purified by HPLC.3
Blood samples (10 ml) were drawn by
syringe from an indwelling heparin lock and
placed into heparinized Vacutainer tubes. The
contents of the tubes were gently mixed and
immediately placed in an ice bath at 4°. Plasma
was separated by centrifugation for 10 min at
2000 rpm. At least 3 ml plasma was withdrawn,
placed in capped glass containers, and frozen at
20° for later assay (nitrofurantoin is stable in
urine and plasma at 200).2
The subjects were instructed to empty their
bladders at the end of each collection period.
The total volume and pH of each urine sample
were measured and recorded. Two 10-ml ali-
quots of each urine sample were then placed in
capped polypropylene containers and immedi-
ately placed in an ice bath at 4°. One aliquot of
each urine sample was assayed immediately for
aminofurantoin. The second aliquot was frozen
at 20° for subsequent assay of nitrofurantoin.
Previous experiments had established that
aminofurantoin was unstable in solution." In
Volume 29 Nitrofurantoin disposition 811
Number 6

Table II. Bioavailability of nitrofurantoin (mei min)

AUC
Subject Treatment (mg!! min) F0* A (mg) Put
1 Oral-fasting 55.4 0.68 11.7 0.72
Oral-food 56.8 0.71 22.3 0.95
IV infusion 72.2 13.1
2 Oral-fasting 57.9 0.85 12.0 0.57
Oral-food 70.2 1.04 19.6 0.79
IV infusion 59.5 26.8
3 Oral-fasting 64.9 0.84 21.6 0.77
Oral-food 76.1 0.99 19.0 0.77
IV infusion 67.6 26.5
4 Oral-fasting 74.9 1.00 10.8 0.72
Oral-food 71.2 0.95 16.2 0.80
IV infusion 75.5 24.9
5 Oral-fasting 75.5 1.01 19.4 0.98
Oral-food 65.2 0.88 18.8 0.80
IV infusion 65.3 18.4
6 Oral-fasting 51.9 0.80 17.4 0.85
Oral-food 68.5 1.06 15.3 0.95
IV infusion 59.7 17.1
Oral-fasting 63.2 (10.3) 0.87 (0.13) 15.5 (4.6) 0.77 (0.14)
R (SD) Oral-food 68.0 (6.6) 0.94 (0.13) 18.5 (2.5) 0.86 (0.09)
IV infusion 66.6 (6.5) 21.1 (5.7)
AUCorp, Doseiv
*Fp
AUC,v Dose,p,

(Dose, - (AUCoppi) +
Au or.1
AUCIv
.33
fFm.
Dosepral

our study the t1/2 of an aqueous solution of
aminofurantoin at room temperature under fluo-
rescent room lights was about 4 hr. Urine was
therefore kept on ice and assayed immediately
after the collection for aminofurantoin. Both
plasma and urine samples were protected from
light at all times.
Nitrofurantoin was assayed by an HPLC
method developed in this laboratory.2 The
mobile phase was methanol-0.0l M sodium
acetate (20:80), pH 5.0. This solution was de-
gassed by vacuum filtration through a 0.45-gm
filter (Millipore) before use. After thawing, 500
Al plasma was mixed with 1000 Al acetonitrile
furantoin in each sample was determined by
comparison of the peak height ratio (nitro-
furantoin :furazolidone) to a standard curve that
was linear from 20 to 1000 ng/ml.
Two standard curves were necessary for the
analysis of nitrofurantoin in urine. For low
levels a standard curve that was linear from 50
to 1000 ng/ml was used. After thawing, urine
samples (1000 Al) were combined with 75 aul
water containing 375 ng furazolidone and
mixed well. Injections of 100 to 400 Al were
satisfactory. High levels of nitrofurantoin in
urine were determined using a standard curve
that was linear from 2.5 to 100 p, g/m1 Urine
.

containing 125 ng furazolidone as the internal
standard. The mixture was centrifuged at 2000
rpm for 10 min to precipitate proteins. The su-
pernatant was decanted and concentrated under
nitrogen at ambient temperature. A portion of
the remaining solution (100 to 400 ill) was
injected onto the column. The amount of nitro-
samples (1000 auJ) were combined with 75 ,u1
water containing 75 I.L g furazolidone. A 25-pd
aliquot was injected onto the column. The
amount of nitrofurantoin in each sample was
determined by comparison of the peak height
ratio (nitrofurantoin:furazolidone) to the re-
spective standard curves.
812 Hoener and Patterson Clin. Pharmacol. Ther.
June 1981

Table HI. Peak times and concentration for nitrofuranoin

Plasma Urine

t max Cmax t max* C Ma,* Duration i

Subject Treatment (min) (ng Iml) (min) ( gg I ml) (min)

Fasting 150 292 150 54 120

Food 60 555 90 84 90
2 Fasting 240 340 210 26 0
Food 180 709 210 51 60
3 Fasting 60 551 45 226 150
Food 120 294 210 65 180
4 Fasting 73 659 90 320 120
Food 240 176 210 18 0
5 Fasting 240 324 90 68 60
Food 75 214 90 34 60
6 Fasting 61 399 45 95 90
Food 240 616 210 50 60
(S D ) Fasting 137 (86) 428 (146) 105 (64) 132 (116) 90 (54)
Food 153 (80) 427 (227) 170 (62) 50 (23) 80 (53)
*Midpoint of collection interval.
tTime above minimum effective concentration, 32 ii.g/m1.4'

Aminofurantoin was assayed by a mod-
ification of the HPLC assay developed in this
laboratory.'7 The mobile phase was metha-
nol-0.02 M sodium acetate (2.5 97.5), pH 3.5.
: trogen to maintain approximately 45 mbar CO,
This solution was degassed by vacuum filtration
through a 0.45-/Lm filter (Millipore) before use.
Urine samples (1000 ,u1) were combined with
30 ILI water containing 3.75 ,ug 5-nitro-2-furoic
acid as the internal standard. A 200-p,1 aliquot
of this solution was injected onto the column.
The amount of aminofurantoin in each sample
was determined by comparison of the peak
height ratio (aminofurantoin:5-nitro-2-furoic
acid) to a standard curve that was linear from
0.1 to 5 g/ m1.
Serum protein binding. Serum protein bind-
ing of nitrofurantoin was determined in each
subject. Fresh blood samples (50 to 60 ml) were
drawn by venipuncture in untreated glass cul-
ture tubes. Blood was allowed to clot at room
temperature for 60 min, then was centrifuged
for 10 min at 2000 rpm to separate the serum.
Serum was decanted and stored at 4° until use.
Protein binding was determined at nitrofuran-
toin concentrations of 100 and 500 ng/ml serum
by ultrafiltration using a 25-mm stirred cell and
filters of 25,000 g/mole nominal molecular
weight limit (Millipore). The cell was housed in
a 37° oven throughout the experiment. Serum
was prewarmed to 37° for 30 mm before the
experiment. Solutions were filtered at a pressure
of 3.5 bar using a mixture of 1.3% CO, in ni-
pressure above the serum samples. Because ni-
trofurantoin binds to the filters, they were
preequilibrated with 10 ml 0.01 M phosphate
buffer, pH 7.4, containing 40% to 50% of the
serum nitrofurantoin concentration. This pre-
caution allowed equilibrium binding values to
be achieved before a significant amount of
serum was filtered. The concentration of nitro-
furantoin was determined by HPLC. A standard
curve was constructed using unfiltered solutions
of nitrofurantoin in 0.01 M phosphate buffer,
pH 7.4. The unbound fraction of nitrofurantoin
(a) was calculated as the nitrofurantoin con-
centration in the filtrate divided by the total
concentration added. Percent bound to serum
protein was calculated as (1 a) X 100%.
Blood-plasma ratio. Fresh blood samples
(10 ml) were collected and incubated with 100
ng/ml nitrofurantoin for 30 min at 37°. Each
sample was then divided into plasma or whole
blood, and the internal standard was added.
Aliquots were assayed as described above.
The peak height ratio blood:peak height ratio
plasma is the blood: plasma ratio.
Data analysis. Computer fitting of the data
Volume 29 Nitrofurantoin disposition 813
Number 6

Table IV. Fraction of dose excreted in urine as metabolite*

Amino Unidentifiedt

Subject Oral-fasting Oral-food IV infusion Oral-fasting Oral-food IV infusion

1 0.016 0.011 NA 0.005 0.005 NA

2 NA 0.017 0.012 NA 0.006 0.006
3 0.012 NA 0.018 0.005 NA 0.007
4 0.009 0.008 0.012 0.004 0.002 0.009
5 0.010 0.018 0.015 0.005 0.008 0.007
6 0.010 0.009 0.013 0.003 0.005 0.005
(SD) 0.012 0.012 0.014 0.004 0.005 0.007
(0.003) (0.005) (0.003) (0.001) (0.002) (0.001)
5A/dose: All parameters were adjusted for the molecular weights of the parent-metabolite.
tCalculated assuming a molecular weight equivalent to the amino metabolite.
NA, Not assayed.

was done on PROPHET using DRUGFUN." of nitrofurantoin with food or on a fasting

Statistical analysis was by paired t test.'" Data
are reported as5"( -± SD.
Results
Percent nitrofurantoin bound to plasma pro-
tein was 62.7 ± 1.5% at the low concentration
and 60.3 ± 6.8% at the high concentration.
The blood:plasma ratio was 0.76 ± 0.06.
Nitrofurantoin kinetics. The plasma levels
of nitrofurantoin after a 50-mg intravenous in-
fusion over 45 min could be described in all
subjects by a two-compartment body model
with zero-order input and first-order elimina-
tion. The calculated kinetic parameters are pre-
sented in Table I. After oral doses on a fasting
stomach the plasma level curves of subjects 3,
4, 5, and 6 could be described by a two-
compartment body model with first-order ab-
sorption and elimination, but a two-compart-
ment body model with zero-order absorption
and first-order elimination was needed to de-
scribe the data for subjects 1 and 2. After oral
doses with food only the data from subjects 1
and 3 could be described with the two-
compartment body model with first-order ab-
sorption and elimination. The absorption data
from the other subjects could not be fitted to any
standard kinetic model. The renal clearance and
fraction excreted unchanged in the urine for the
oral data are reported in Table I. The plasma
concentration time curves for subjects 5 and 6
are shown in Fig. 1.
Bioavailability of nitrofurantoin. The abso-
lute of bioavailability after oral administration
stomach for each of the subjects is presented in
Table II. A paired t test showed no significant
differences between the food or fasting condi-
tions in extent of availability calculated from
the plasma and the urine data.
The relative rates of availability of nitrofuran-
toin from the oral tablet dosage form with food
or on a fasting stomach may be assessed from
the time to reach the maximum concentration in
either plasma or urine. The tmax and correspond-
ing Cmax levels are shown in Table HI. A paired
t test revealed no statistically significant differ-
ences between the food and fasting conditions.
The length of time the urine concentration was
above the minimum effective concentration, 32
Ag/m1,45 is reported in Table III.
Metabolites. Table IV presents the fraction
of the dose excreted in the urine as the amino or
an unidentified metabolite. It is possible but not
confirmed that based on its ultraviolet spectra
and HPLC behavior this unknown metabolite is
the acetylated conjugate of aminofurantoin. It
can be seen that there is no significant differ-
ence in the fraction of the dose excreted as
either metabolite following intravenous or oral
administration of the parent nitrofurantoin.
Discussion
We have defined nitrofurantoin kinetics in six
subjects after a 45-min intravenous infusion of
50 mg. The data could be described by a two-
compartment open-body model with a rapid
distribution phase and a slower elimination
phase with a terminal t1/2 of 58.1 ± 15 min.
814 Hoener and Patterson
This t1/2 is considerably longer than the 15 to 40
min reported by other investigators.8, 22, 28, 29, :35
Because of assay limitations, earlier studies
have not been able to follow the plasma and
urine levels of the nitrofurantoin long enough to
characterize a second compartment. With the
exception of the hybrid distribution rate con-
stant a and the volume of the central compart-
ment V1, the other kinetic parameters (Table I)
determined after intravenous doses are notable
for their relatively small intersubject variability,
but the long infusion time and the relatively
short distribution t1/2 make the estimation of a
and V, uncertain.
Table I indicates that the average fraction of
the dose excreted unchanged is 0.34 when given
orally on a fasting stomach, 0.34 when given
orally with food, and 0.47 after intravenous in-
fusion. Bioavailability studies of nitrofurantoin
tablets made from the microcrystalline form of
the drug have recovered from 15% to 60% of an
oral dose as unchanged drug in the urine.* In a
study of the effects of food on the bioavailabil-
ity of the macrocrystalline capsules, the fraction
excreted unchanged rose from 0.20 to 0.40
when the capsule was taken with food,4. 36 but
in the same study the effect of food on the mi-
crocrystalline tablet was smaller, from 0.36 to
0.44.4. "6 This change is of the same order as in
our study in which food had no effect on the
fraction excreted unchanged in the urine.
Because all subjects received the intravenous
infusion, we were able to calculate the avail-
ability of nitrofurantoin after oral doses. The
plasma data in Table II indicate that the average
absolute availability of nitrofurantoin is about
90%. When the urine data are corrected for the
day-to-day variation in renal clearance,'" the
availability calculated from the amount excreted
unchanged in urine gives compatible results.
There are no statistically significant differences
between the food and fasting conditions. It ap-
pears that nitrofurantoin is well absorbed after
taking the tablet.
The inter- and intrasubject uniformity in the
intravenous kinetic parameters and oral avail-
ability data is not reflected in the absorption
*References 1, 4, 8, 12, 14, 16, 20, 22, 23, 26, 29-32, 35, 36,
39, 41, 42.
Pharmacol. Ther.
June 1981
process. As Table HI indicates, the time to peak
and the maximum concentration in both plasma
and urine are variable, and the nitrofurantoin
was not always more rapidly available when
taken on a fasting stomach. Two extreme cases
are shown in Fig. 1. Subject 5 had much slower
absorption fasting, and subject 6 had much
slower absorption with food. The curves also
indicate the possibility of a considerable lagtime
when absorption is slow. Complex absorption
patterns were also seen in the other subjects,
making it difficult to describe the oral plasma
or urine levels with the conventional kinetic
models.
Using urine data to assess the duration of
pharmacologic response suggests a much differ-
ent assessment of what might be happening than
merely measuring the extent of availability. If
we accept 32 ktg/m1 as the minimum effective
concentration ,45two subjects never achieved this
level (Table III). In the other four subjects the
duration ranged from 60 to 180 min.
Two precautions must be observed. First, 50
mg is on the low end of the recommended dos-
ing regimen; and second, these urine concen-
trations may not adequately reflect the concen-
tration at the site of action. We conclude that,
although nitrofurantoin appears to be nearly
completely absorbed after oral doses, the ab-
sorption is erratic. Unpredictable behavior may
lead to inadequate urine concentrations.
Recent studies have indicated that nitrofuran-
toin is mutagenic in bacterial and mammalian
tissue culture test systems .15, 21, 27, 43 In long-
term animal feeding studies nitrofurantoin, un-
like most other nitrofuran derivatives, was
noncarcinogenic .9-11 There is, nevertheless,
concern about the potential risk in humans.
Mutagenic effects of the nitrofurans apparently
result from the ability of activated reduced me-
tabolites to bind covalently to DNA.7' 24' "4
Others have attributed its pulmonary and he-
patic toxicity to the metabolites.* Because we
could not measure metabolites bound to DNA,
we attempted to determine whether nitrofuran-
toin had been metabolically reduced by quan-
tifying the amino metabolite in urine. We also
detected in urine an unknown metabolite, which
*References 6, 13, 19, 24, 37, 40, 44.
Volume 29
Number 6
we suspect to be the acetylated amino metabo-
lite. As indicated in Table IV, a little more than
1% of the dose was excreted in the urine as
aminofurantoin. The aminofurantoin is not it-
self mutagenic in bacterial test systems21; it is,
however, the end product of a series of reactive
intermediates that may bind to DNA or pro-
teins. The long-term risk potential cannot be
evaluated from our data. We have shown that
metabolic reduction occurs in humans.
References
Albert KL, Sedman AJ, Wilkinson P, Stoll RG,
Murray WJ, Wagner J: Bioavailability studies of
acetaminophen and nitrofurantoin. J Clin Phar-
macol 5:264-270, 1974.
Aufrere MB, Hoener B, Vore ME: High per-
formance liquid chromatographic assay for ni-
trofurantoin in plasma and urine. Clin Chem
23:2207-2212, 1977.
Aufrere MB, Hoener B, Vore ME: Reductive
metabolism of nitrofurantoin in the rat. Drug
Metab Dispos 6:403-411, 1978.
Bates TR, Sequeira JA, Tembo AV: Effect of
food on nitrofurantoin absorption. CLIN PHARM
THER 16:63-68, 1974.
Benet LZ, Galeazzi RL: Noncompartmental de-
termination of steady-state volume of distribu-
tion. J Pharm Sci 68:1071-1074, 1979.
Black M, Rabin L, Schatz N: Nitrofurantoin-
induced chronic active hepatitis. Ann Intern
Med 92:62-64, 1980.
Boyd MR, Stiko AW, Sasame HA: Metabolic
activation of nitrofurantoin. Biochem Pharmacol
28:601-606, 1979.
Bron J, Vree TB, Damsma JE, Hekster YA,
Van der Klein E: Dissolution, bioavailability
and pharmacokinetics of three nitrofurantoin
preparations in man. Arzneim Forsch 29:1614-
1620, 1979.
Cohen SM: Toxicity and carcinogenicity of ni-
trofurans, in Bryan GT, editor: Nitrofurans.
New York, 1978, Raven Press.
Cohen SM, Erturk E, Von Esch AM, Crovetti
AJ, Bryan GT: Carcinogenicity of 5-nitrofurans,
5-nitroimidazoles, 4-nitrobenzenes, and related
compounds. J Natl Cancer Inst 51:403-417,
1973.
Cohen SM, Erturk E, Von Esch AM, Crovetti
AJ, Bryan GT: Carcinogenicity of 5-nitrofurans
and related compounds with amino-heterocyclic
substituents. J Nail Cancer Inst 54:841-850,
1975.
Conklin JD, Hailey MD: Urinary excretion in
man during oral dosage of different nitrofuran-
toin formulations. CLIN PHARM THER 10:534-
539, 1969.
Nitrofurantoin disposition 815
Geller M, Flaherty DK, Dickie HA, Reed CE:
Lymphopenia in acute nitrofurantoin pleuropul-
monary reactions. J Allergy Clin Immunol
59:445-448, 1977.
Gladigau VV, Gebhardt U: In vitro and in vivo
Untersuchungen mit vershieden Galenischen zu-
bereitungsformen von nitrofurantoin. Arneim
Forsch 28:1771-1778, 1978.
Goodman DR, Hakkinen PJ, Nemenzo J, Vore
M: Mutagenic evaluation of nitrofuran deriva-
tives in Salmonella typhimurium , by the mi-
cronucleus test, and by in vivo cytogenetics.
Mutat Res 48:295-306, 1977.
Gromotza R, Bruhl W, Schmid E: Improved
treatment of chronic pyelonephritis with nitrofu-
rantoin in combination with deglycyrrhizinated
liquorice. Arneim Forsch 22:627-629, 1972.
Hoener B. Wolff JL: High performance liquid
chromatographic assay for the metabolites of ni-
trofurantoin in plasma and urine. J Chromatogr
182:246-251, 1980.
Holford N: DRUGFUN, in Perry HM, Wood JJ,
editors: Public procedures notebook. Cam-
bridge, Mass., 1979, Bolt Beranek and Newman.
Jacknowitz Al, LeFroch JL, Prince RA: Nitrofu-
rantoin polyneuropathy: Report of two cases.
Am J Hosp Pharm 34:759-762, 1977.
Jaffe JM: Effect of propantheline on nitrofuran-
toin absorption. J Pharm Sci 64:1729-1730,
1975.
Klemincic JM, Wang CY: Mutagenicity of ni-
trofurans, in Bryan GT, editor: Nitrofurans.
New York, 1978, Raven Press.
Maier-Lenz H, Ringwelski L, Windorfer A:
Comparative pharmacokinetics and bioavaila-
bility for different preparations of nitrofurantoin.
Arzneim Forsch 29:1898-1901, 1979.
Mannisto P: The effect of crystal size, gastric
content and emptying rate on the absorption of
nitrofurantoin in healthy human volunteers. Int J
Clin Pharmacol 16:223-228, 1978.
Mason RP, Holtzman JL: The role of catalytic
superoxide formation in the 02 inhibition of
nitro-reductase. Biochem Biophys Res Comm
67:1267-1274, 1975.
Mattok GL, Hossie RD, McGilveray IJ: In vi-
vo:in vitro studies of nitrofurantoin tablets. Can
J Pharm Sci 7:84-87, 1972.
Mazza A, Hecht-Lucari G: Urinary excretion,
blood levels and toxicity in humans of the
sodium salt of N-(5-nitro-2-furfurylidene)-
1-amino-hydantoin when given by the intramus-
cular and intravenous routes. Antibiot
Chemother 11:434-437, 1960.
McCalla DR, Voutsinos D: On the mutagenicity
of nitrofurans. Mutat Res 26:3-16, 1974.
McGilveray IJ, Mattok GL, Hossie RD: A study
of the bioavailabilities and dissolution rates of
commercial tablets of nitrofurantoin. J Pharm
Pharmacol 23:246S, 1971.
816 Hoener and Patterson
McGilveray Ii, Mattok GL, Hossie RD: The
comparison of bioavailabilities of commercial
nitrofurantoin tablets. Rev Can Biol 32:99-106,
1973.
Mendes RW, Masih SZ, Kanumuri RR: Effect
of formulation and process variables on bio-
equivalency of nitrofurantoin. H. In vivo-in vitro
correlations. J Pharm Sci 67:1616-1619, 1978.
Meyer MC, Slywka GWA, Dann RE, Whyatt
PL: Bioavailability of 14 nitrofurantoin prod-
ucts. J Pharm Sci 63:1693-1697, 1974.
Naggar VF, Khalil SA: Effect of magnesium
trisilicate on nitrofurantoin absorption. CLIN
PHARM THER 25:857-863, 1979.
Oie S, Jung D: Bioavailability under variable
renal clearance conditions. J Pharm Sci 68:
128-129, 1979.
Olive PL: Macromolecular, antineoplastic and
radiosensitization effects of nitrofurans, in Bryan
GT, editor: Nitrofurans. New York, 1978,
Raven Press.
Reckendorf HK, Castringius RG, Spingler HK:
Comparative pharmacodynamics, urinary ex-
cretion, and half-life determinations of nitrofu-
rantoin sodium. Antimicrob Agents Chemother
1962:531-537, 1963.
Rosenberg HA, Bates TR: The influence of food
on nitrofurantoin bioavailability. CLIN PHARM
THER 20:227-232, 1976.
Sasame HA, Boyd MR: Superoxide and hydro-
gen peroxide production and NADPH oxidation
stimulated by nitrofurantoin in lung microsomes:
Possible implications for toxicity. Life Sci
24:1091-1096, 1979.
Schirmeister J, Stefani F, Willmann H, Hallaner
Clin. Phurmucol. Ther.
June 1981
W: Renal handling of nitrofurantoin in man.
Antimicrob Agents Chemother 1965:223-226,
1966.
Seager H: The effect of methylcellulose on the
absorption of nitrofurantoin from the gastroin-
testinal tract. J Pharm Pharmacol 20:968-969,
1968.
Sharp JR, Ishak KG, Zimmerman HJ: Chronic
active hepatitis and severe hepatic necrosis as-
sociated with nitrofurantoin. Ann Intern Med
92:14-19, 1980.
Soci MM, Parrott EL: Influence of viscosity on
absorption from nitrofurantoin suspensions. J
Pharm Sci 64:403-406, 1980.
Stoll RG, Bates TR, Swarbrick J: In vitro dis-
solution and in vivo absorption of nitrofurantoin
from deoxycholic acid coprecipitates. J Pharm
Sci 62:65-68, 1973.
Tazima Y, Kada T, Murakami A: Mutat Res
32:55-80, 1975.
Tolman KG: Nitrofurantoin and chronic active
hepatitis. Ann Intern Med 92:119-120, 1980.
Turck M, Ronald AR, Petersdorf RG: Suscepti-
bility of Enterobacteriaceue to nitrofurantoin
correlated with eradication of bacteriuria.
Antimicrob Agents Chemother 1966:446-452,
1967.
United States Pharmacopeia XX: Nitrofurantoin
tablets. Rockville, Md., 1980, U.S. Phar-
macopeial Convention.
Wilkinson GR, Shand DG: A physiological ap-
proach to hepatic drug clearance. CLIN PHARM
THER 18:377-390, 1975.
ZarJH: Biostatistical analysis. Englewood Cliffs,
N. J., 1974, Prentice-Hall.