Full text of DOI:10.1592/phco.21.7.669.34574

Active Transport of Nitrofurantoin into Human Milk
Phillip M. Gerk, Pharm.D., Ph.D., Robert J. Kuhn, Pharm.D., Nirmala S. Desai, MBBS, and
Patrick J. McNamara, Ph.D.
Study Objective. To determine the extent to which nitrofurantoin is
transferred into human milk.
Design. Prospective, single-dose pharmacokinetic study.
Setting. University-affiliated clinical research center.
Patients. Four healthy lactating women 8–26 weeks postpartum.
Inter vention. All subjects received a single, oral, 100-mg dose of
nitrofurantoin macrocrystals with food. Serial serum and milk samples
were obtained and analyzed by high-performance liquid chromatography.
Measurements and Main Results. Milk pH, milk fat partitioning, and protein
binding in serum and milk were determined. Predicted milk:serum ratio
(
M:S) was compared with the observed M:S. Nitrofurantoin M:S predicted
was 0.28 ± 0.05, whereas M:S observed was 6.21 ± 2.71. Average milk
concentration was 1.3 mg/L, and estimated suckling infant dosage was 0.2
mg/kg/day or 6% of maternal dose (mg/kg).
Conclusions. Nitrofurantoin is actively transported into human milk,
achieving concentrations in milk greatly exceeding those in serum.
Concern is warranted for suckling infants younger than 1 month old, or for
infants with a high frequency of glucose-6-phosphate dehydrogenase
deficiency or sensitivity to nitrofurantoin.
(
Pharmacotherapy 2001;21(6):669–675)
Nitrofurantoin is a weakly acidic drug with a
pKa of 7.2. Being actively excreted in the renal
tubule, it is bacteriostatic or bactericidal in the
urine, depending on concentration. It is not
useful for systemic infections because of low
uncomplicated urinary tract infections. Reports
differ with regard to the extent of transfer of
3
–5
nitrofurantoin into human milk ; the American
Academy of Pediatrics classified the agent as6
usually compatible with breastfeeding.
However, patients receiving nitrofurantoin may
have rare but serious side effects such as chronic
1
concentrations in the blood. The nitrofurantoin
macrocrystalline formulation remains one of the
top 200 prescription drugs in the United States,
7
8
liver disease, cholestatic hepatitis, or hemolytic
anemia in glucose-6-phosphate dehydrogenase–
2
with almost 4,000,000 prescriptions in 1999. It
9
is prescribed for lactating women to treat
deficient patients. Therefore, nitrofurantoin
transfer into milk remains a clinical concern.
Breastfeeding has many benefits, providing
passive immunity, various growth hormones, and
From the Division of Pharmaceutical Sciences and
Division of Pharmacy Practice and Science, College of
Pharmacy (Drs. Gerk, Kuhn, and McNamara), and the
Department of Pediatrics, College of Medicine (Dr. Desai),
University of Kentucky, Lexington, Kentucky.
10
a more favorable nutritive content. Recently,
some studies even suggested that breastfed
infants have an advantage in cognitive
Supported by the University of Kentucky Women ’s Health
Initiative, and U.S. Public Health Service (grant
1
1, 12
development.
According to the Ross
#
M01RR02602).
Laboratories Mothers’ Survey, breastfeeding was
started in 14% more mothers and was continued
for 6 or more months in 19.3% more mothers in
Address reprint requests to Patrick J. McNamara, Ph.D.,
Division of Pharmaceutical Sciences, Room 401A Pharmacy
Building, University of Kentucky College of Pharmacy,
Lexington, KY 40536-0082.
1
3
1995 compared with 1989.
However, the

6
70
PHARMACOTHERAPY Volume 21, Number 6, 2001
increase in breastfeeding over recent years has
brought increased concern about the inadvertent
transfer of drugs and other substances into breast
milk. Some of these agents have caused serious
20–40 years, were selected from the University of
Kentucky Medical Center. Exclusion criteria
were significant medical histories, concurrent
drugs, previous adverse reactions to nitro-
furantoin, and concurrent caffeine, alcohol, or
tobacco use. The subjects refrained from
breastfeeding for 24 hours after the dose of
nitrofurantoin was administered.
1
4
consequences or even death in the neonate.
Also, the lack of information on transfer of
substances into milk may cause fear of the
potential consequences of ingestion, leading to
1
5
cessation of breastfeeding. Thus, it is necessary
to know the exposure of the suckling infant to
maternal drugs and toxins.
Prediction of M:S
Before administration of nitrofurantoin, milk
and blood samples were obtained from the
subjects. The milk was placed on ice until
analysis, and blood drawn from a forearm venous
catheter was allowed to clot and centrifuged to
obtain serum. Measurements of milk pH were
determined anaerobically at 37°C within 1 hour
of collection on a clinical blood gas analyzer.
The unbound fractions in the milk were
determined by equilibrium dialysis as follows.
Skim milk was obtained by placing 200-µl
aliquots of whole milk in a polyethylene tube and
centrifuging in a Beckman Microfuge B (Beckman
Instrument Co., Palo Alto, CA) for 30 seconds at
room temperature. The polyethylene tubes were
sliced with a razor to separate the cream from the
whey, the casein pellet was resuspended, and
skim milk was harvested. The skim milk was
To predict neonatal exposure from the transfer
of drugs into breast milk, a passive diffusional
model was developed. The model assumes that
only unbound, unionized drug freely equilibrates
across the mammary epithelium. Therefore, drug
ionization (a function of drug pKa and pH of
milk and serum), milk and serum protein
binding, and milk fat partitioning are taken into
1
6
account. Using this model, milk:serum ratios
1
7
(
M:S) may be predicted for many agents.
Although the diffusion model may predict M:S
for many drugs, other drugs may be actively
transported, reaching M:S ratios greater than
predicted by passive diffusion. Cimetidine and
nitrofurantoin are actively transported into rat
1
8, 19
milk,
and active transport of cimetidine into
2
0
human milk has been demonstrated.
In
addition, other agents are actively transported
into the milk of other species, such as rats, goats,
14
spiked with C-nitrofurantoin 100 disinte-
grations per minute (dpm)/µl (Chemsyn, Lexena,
KS); and 250 µl were loaded into the equilibrium
dialysis apparatus (Bel-Art Products, Pequannock,
NJ) assembled with Spectra/Por 1 regenerated
cellulose dialysis membrane, 6000–8000
molecular weight cutoff (Spectrum Laboratories,
Inc., Rancho Dominguez, CA). The milk samples
were dialyzed against a 133-mM phosphate
buffer; pH was adjusted to match the milk pH
measured for each subject. The apparatuses were
placed in a rotating water bath at 37°C for 6
hours (corresponding to approximately 95%
steady-state for both milk and serum) and
protected from light. Aliquots of 50 µl of both
the buffer and the spiked skim milk were
counted by mixing with 3a70B liquid
scintillation cocktail (Research Products
International Corp., Mt. Prospect, IL) and
counting on a Tri-Carb 2200CA liquid
scintillation counter (Packard Instrument,
Meriden, CT). After subtracting background, the
3
, 18–26
and cows.
However, the extent to which
nitrofurantoin is transferred into human milk
and whether it involves an active transport
process are not known. This study was done to
determine the extent to which nitrofurantoin
enters human milk, and thereby to implicate
either a passive (diffusional) or active
(
concentrative) transport process. To use the
diffusion model, the unbound and the unionized
fractions for serum and milk, as well as the
skim:whole milk ratio, were determined from
lactating mothers. The results obtained were
compared with the M:S ratio observed in vivo.
An understanding of the types of agents actively
transported into human milk may help develop
better models to predict M:S more accurately for
certain drugs.
Methods
Study Design and Experimental Protocol
1
4
quotient of C-nitrofurantoin dpm in the buffer
and the spiked skim milk yielded the fraction
unbound in skim milk. The unbound fraction in
The clinical research protocol was approved by
the University of Kentucky Chandler Medical
Center institutional review board. Four healthy
lactating women 8–26 weeks postpartum, aged
1
4
the serum was determined similarly, using C-
nitrofurantoin–spiked serum dialyzed against a

NITROFURANTOIN IN HUMAN MILK Gerk et al
33-mM phosphate buffer pH 7.40. The skim to
671
1
MA) preconditioned by washing with 3 ml
ethanol, 3 ml acetonitrile, and then triplicate
washings with 3 ml water. The sample was then
loaded onto the C18 solid-phase extraction
column, eluted with acetonitrile, evaporated
under nitrogen, and reconstituted with mobile
phase. The sample was injected onto a Shimadzu
HPLC system (Kyoto, Japan) having a Lichrosorb
5 RP18 125 x 4.0 mm column (Phenomenex,
Torrance, CA) and eluted with 10% acetonitrile
and 90% 25 mM potassium phosphate buffer (pH
3.0) at 1.0 ml/minute. Ultraviolet absorbance
was measured at 366 nm. Peak height ratios
(nitrofurantoin:furazolidone) were used for
comparison with the standard curve. The
extraction efficiency was 70–95%, the limit of
quantification was 0.01 µg/ml, and the intra- and
interday coefficients of variation were less than
whole partitioning was determined by spiking
1
4
whole milk with C-nitrofurantoin, then
comparing it with an aliquot centrifuged as noted
to obtain skim milk. Equation 1 was used to
calculate predicted M:S. The radiochemical
purity on the buffer side after dialysis was
determined by high-performance liquid
chromatography (HPLC) for one milk and serum
sample.
u
f f
s s
[
M/S]predicted = —————
Eq. 1
u
f f (S/W)
m m
where M/S
is the predicted milk:serum
predicted
u
u
ratio; f and f are the unionized fractions of the
s
m
drug in serum or milk, respectively; f and f are
s
m
the unbound fractions in serum or milk; and S/W
is the skim:whole milk drug concentration ratio.
1
5%.
Determination of Observed M:S
Pharmacokinetic Analysis
Subjects were admitted to the University of
Kentucky General Clinical Research Center and a
forearm venous catheter was placed. After the
initial blood and milk samples were obtained, the
subjects consumed a 100-mg capsule of
nitrofurantoin macrocrystals (Geneva,
Broomfield, CO) with a standardized high-fat
breakfast consisting of a McDonald’s Egg
McMuffin, sausage (or a fat-equivalent
substitute), and 250 ml orange juice. Venous
blood samples (5 ml) were drawn from the
venous catheter at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12
hours after the dose. Serum was harvested from
each blood sample, aliquoted, and stored frozen.
Milk samples were collected from alternating
breasts using an Egnell LACT-E electric breast
pump (Egnell, Cary, IL) immediately after
obtaining venous samples, with complete
collections every 4 hours for 12 hours. The milk
was aliquoted and stored frozen. All samples
were protected from light at all times.
Area under the concentration-time curve
(AUC) during the sampling period was
determined using noncompartmental methods,
and AUC to infinity was estimated by dividing
the last concentration by the elimination rate
constant obtained from the last two quantified
concentrations. Observed M:S values were
determined as in Equation 2 using total AUCs.
Truncated AUCs were determined to the time of
the last quantified sample. Peak concentrations
and times to peak were determined by inspection
of milk and serum concentration-time curves for
each subject.
0–∞
AUC
milk
[M/S]observed = ————
Eq. 2
0
–∞
AUC
serum
Statistical Analysis
To detect an active transport mechanism
creating at least a 2-fold difference between
predicted M:S and observed M:S, 95% confidence
HPLC Analysis
2
7
intervals (CIs) were constructed around 50%
and 200% of the predicted M:S. If the 95% CI for
the observed M:S did not include values
encompassed by the 95% CI of 50–200% of the
predicted M:S, then the null hypothesis (that
passive diffusion predominated) was rejected and
the alternate hypothesis (that active transport
predominated) was accepted. An observed M:S
value above the upper limit of this range (or
below the lower limit) would indicate that
nitrofurantoin was actively transported into (or
out of) the milk.
The samples were assayed using a method that
1
8
was modified. To each 0.5-ml aliquot of serum
or milk, 1 µg/ml furazolidone HCl (50 µl of 10
µg/ml) was added as an internal standard. Serum
samples were acidified and proteins precipitated
by adding 50 µl of 1 N HCl. Fifty microliters of
water were added to milk samples. All samples
were vortexed for 15 seconds. Solid-phase
extraction was then performed using octadecyl
(
2
C18) solid-phase extraction columns (#9002,
00 mg, Becton-Dickinson Labware, Bedford,

6
72
Results
Figure 1 shows the average serum and milk
PHARMACOTHERAPY Volume 21, Number 6, 2001
Discussion
This study showed an M:S observed for
nitrofurantoin more than 20-fold above the M:S
predicted by the diffusion model, indicating
active transport of nitrofurantoin into human
milk. This finding indicates that nitrofurantoin
is actively transported into human milk, reaching
concentrations in milk much greater than in
serum. Active transport of cimetidine into
human milk was also demonstrated by our
laboratory, with an M:S observed about 5.5 times
concentrations of nitrofurantoin versus time after
a single, 100-mg, oral dose of nitrofurantoin
macrocrystals. The concentrations in milk are
greater than those in serum at each time point.
Table 1 shows the pharmacokinetic parameters of
nitrofurantoin and results of determining M:S
observed. For subjects 1 and 2, samples at 3 and
1
0 hours postdose were not obtained. No
differences in time to peak serum and milk
concentrations were observed in this study. Table
2
0
greater than predicted.
With regard to
2
shows the determinants of M:S predicted,
nitrofurantoin and cimetidine, active transport
into both rat and human milk for each agent now
namely the milk pH, milk and serum protein
binding, and the milk fat partitioning
18–20
has been shown.
(
skim:whole milk ratio). After 6 hours of
The data from this study suggest that the mean
nitrofurantoin milk concentration during each
dialysis, the radiochemical purity in the buffer as
measured by HPLC was 91.3% for the dialyzed
milk and 94.6% for the dialyzed serum. The
fraction unbound in milk (0.94 ± 0.03) was
much greater than the fraction unbound in
serum (0.34 ± 0.02); the skim:whole milk ratio
approached unity. The M:S predicted was 0.28 ±
1
2-hour dosing interval is approximately 1.3
mg/L. If an infant consumes 150 ml/kg/day of
28
milk, and if a 60-kg mother takes nitrofurantoin
macrocrystals 100 mg twice/day, then the infant
would consume 0.2 mg/kg, or approximately 6%
of the maternal dose (mg/kg) each day. Although
nitrofurantoin has caused hemolytic anemia and
0
.05, consistent with a nonlipophilic organic
anion, whereas M:S observed was 6.2 ± 2.7. The
M:S observed was 22-fold greater than the M:S
predicted on average, and the 95% CIs around
M:S observed (3.6–8.9) did not overlap the 95%
CIs surrounding the range of 50–200% of M:S
predicted (0.12–0.64). The mean observed M:S
between truncated and total AUCs had a less
than 5% difference. Mean nitrofurantoin milk
concentration of 1.3 mg/L was determined by
dividing the truncated milk AUCs by the time of
the last quantified milk samples.
7, 9
chronic active hepatitis in some patients, this
low exposure should minimize clinical problems.
In our study, the absorption of nitrofurantoin
appears to be prolonged compared with other
studies. Our study found a peak time of 4–6
hours, whereas other studies with nitrofurantoin
3
,
macrocrystals showed a peak time of 1–3 hours.
2
9, 30
This difference is thought to be caused by
the breakfast administered before the dose. Our
study breakfast was high in fat content, which
may have altered the bioavailability and
dissolution kinetics of the macrocrystalline
nitrofurantoin formulation we administered. The
meal was given to increase the extent of
3
1, 32
absorption
and decrease the likelihood of
3
3
nausea and vomiting. Another study showed
that food increases the bioavailability of a
macrocrystalline nitrofurantoin capsule by
3
1
almost 2-fold.
The breakfast we gave had
similar or greater fat content than the one in that
study, consisting of corn flakes, milk, and
3
1
buttered toast. The authors suggested that the
increase in bioavailability could be from
viscosity-increasing effects or lipid content of the
chyme, increasing gastric residence time and
allowing more dissolution time before emptying
into the duodenum, where absorption is
Figure 1. Mean (± SD) milk and serum concentrations in
four lactating women after 100-mg dose of nitrofurantoin
macrocrystals. Samples at 3 and 10 hours were not
obtained for subjects 1 and 2; only the corresponding means
are presented.
3
1
optimal. They also showed an absorption rate-
limited pharmacokinetic profile from a fed
3
1
subject receiving a microcrystalline formulation.

NITROFURANTOIN IN HUMAN MILK Gerk et al
673
Table 1. Pharmacokinetic Parameters of Nitrofurantoin in Milk and Serum of Four Lactating
Women
1
2
3
4
Mean
SD
Milk parameters
Cmax (µg/ml)
Tmax (hrs)
2.13
4
2.15
6
3.32
6
3.22
4
2.71
5
0.65
1.2
Total AUC (µg•hr/ml)
Truncated AUC (µg•hr/ml)
10.6
10.4
19.0
16.1
20.3
19.7
12.8
12.8
14.9
14.8
4.2
4.0
Serum parameters
Cmax (µg/ml)
Tmax (hrs)
0.54
4
0.44
7.4
0.35
4
0.67
4
0.50
4.9
0.14
1.7
Total AUC (µg•hr/ml)
Truncated AUC (µg•hr/ml)
2.43
2.42
3.40
3.07
2.00
1.93
2.54
2.52
2.51
2.48
0.44
0.46
M:S observed
4.34
5.25
10.14
5.04
6.19
2.66
Cmax = maximum concentration; Tmax = time to reach maximum concentration; AUC = area under the
concentration-time curve; M:S = milk:serum ratio.
Table 2. Prediction of Nitrofurantoin M:S in Human Milk and Serum of Four Lactating Women
1
2
3
4
Mean
SD
Milk parameters
Milk pH
Unionized, milk (%)
Unbound, milk (%)
Skim:whole
7.05
7.24
7.36
7.08
7.18
51.0
94.1
1.02
0.15
8.3
3.1
58.3
95.5
1.01
47.7
96.1
1.02
40.7
89.4
1.02
57.1
95.4
1.01
0.01
Serum parameters
Unionized, serum (%)
Unbound, serum (%)
a
38.7
34.1
36.9
0.25
32.7
0.27
33.0
0.34
33.7
0.24
1.9
0.05
M:S predicted
0.28
M:S = milk:serum ratio.
a
Value determined by assuming serum pH = 7.4.
A similar profile resulted when a nitrofurantoin
medium-size crystal (50–80 µm) tablet was given
fraction was 34.1% (Table 2). The higher protein
binding in serum versus milk contributed to a
low predicted M:S, because bound drug is not
free to cross the blood-milk barrier.
Nitrofurantoin is a weak acid, and hence the
unionized fraction in milk was greater than in
serum, favoring reabsorption from milk and
decreasing the predicted M:S. The milk pH
values measured in this study were consistent
with literature values. Finally, the milk fat
partitioning was low, approaching a value of
unity for the skim:whole milk ratio. This was
expected; unionized nitrofurantoin is not
lipophilic and has a calculated logP of -0.54 ±
0.67 for the major tautomer, as determined using
ACD/LogP version 3.6 from the ACD/I-lab
service (Advanced Chemistry Development, Inc.,
Toronto, Canada).
3
0
with a fatty breakfast. However, one investi-
gation did not show absorption rate-limited
kinetics in lactating women receiving a
3
macrocrystalline nitrofurantoin tablet, perhaps
because it did not control the composition of the
meal.
Our study showed prolonged absorption
profiles. As a result, we used only the last two
quantified concentrations to obtain terminal
elimination rate constants, thus introducing
some error into the extrapolated AUCs.
However, the differences in truncated or total
AUCs made little difference in the observed M:S.
The ionization, protein binding, and milk fat
partitioning determined in this study all
contributed to a low predicted M:S. The extent
of protein binding in human milk has not been
reported. Nitrofurantoin is 23–40% unbound in
plasma in humans, but the results vary among
3
5
Other reports of nitrofurantoin transfer into
human milk are conflicting. One study failed to
detect nitrofurantoin in the milk of any patients
taking nitrofurantoin 100 mg 4 times/day from
3
4
studies. In this study, nitrofurantoin was 94.1%
unbound in milk, whereas the serum unbound
5
0–4 days postpartum. That study, though, had

6
74
PHARMACOTHERAPY Volume 21, Number 6, 2001
several apparent problems. First, the milk
secretory processes are not mature until days 5–8
and assistance, and Earl Paxton, Jane Alcorn, Jeff
Edwards, and Fareesh Kanga for their technical
assistance.
3
6
postpartum. Moreover, the assay sensitivity was
5
only 2 µg/ml, which is scarcely enough to detect
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1
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Conclusion
Nitrofurantoin was actively transported into
human milk, reaching concentrations in milk
greatly exceeding those in serum. However, the
inadvertent dose to a suckling infant remains less
than 10% of the maternal dose (mg/kg). Clinical
concern is warranted for suckling infants
younger than 1 month, or for infants with a high
frequency of glucose-6-phosphate dehydrogenase
deficiency or sensitivity to nitrofurantoin.
2
2
2
2
Acknowledgments
The authors thank the University of Kentucky
General Clinical Research Center for their cooperation
2

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