Pharmacokinetics of Ibuprofen

KENNETH S. ALBERT, Ph.D. The pharmacokinetics of ibuprofen (Motrin) are best described by a
CHARLENE M. GERNAAT, R.N. two-compartment open model. Ibuprofen pharmacokinetics are only
Kalamazoo, Michigan minimally influenced by advanced age, the presence of alcoholic
liver disease, or rheumatoid arthritis. Levels of ibuprofen in breast
milk are negligible. In addition, ibuprofen can be combined with ac-
etaminophen without altering the pharmacokinetic profile. However,
although not yet Clinically proved, the concomitant use of ibuprofen
and aspirin appears to reduce ibuprofen plasma levels to less than
half those observed with ibuprofen alone.

Ibuprofen (Motrin, Upjohn), a propionic acid derivative, is a nonsteroidal

anti-inflammatory agent used in the treatment of rheumatoid arthritis, os-
teoarthritis, and mild to moderate pain [1,2]. Introduced in the United
Kingdom in 1969, it was approved for marketing in the United States in
1974. Since its first introduction, ibuprofen has been studied extensively,
and the basic pharmacokinetic properties of the drug are well known.
Although the previously established pharmacokinetic properties of
ibuprofen will be briefly described, the main objective of this report is to
review new and more specific data, particularly with reference to unique
study populations.

ANALYTICAL METHODS
A variety of gas-liquid chromatographic (GLC) [3,4] and high-perform-
ance liquid chromatographic (HPLC) [5-11] methods for measuring
ibuprofen in plasma or serum have been reported. One of these tech-
niques, an electron capture GLC, is sensitive enough to measure
ibuprofen in 0.5 ml of plasma or serum [4]. More recently, a rapid, spe-
cific, and sensitive HPLC method with ultraviolet detection has been de-
veloped for measuring as little as 1 jLg/ml of ibuprofen in as little as 0.1 ml
of biologic fluid [12]. This method has been applied to human capillary
and venous plasma and to saliva after the administration of 400-mg oral
doses of ibuprofen to four normal volunteers. Capillary and venous
From the Clinical Biopharmaceutics Research Unit,
plasma level curves were virtually superimposable (Figure 1). All con-
the Upjohn Company, Kalamazoo, Michigan. Re- centrations of ibuprofen in saliva were well below assay sensitivity, indi-
quests for reprints should be addressed to Dr. Ken- cating that saliva sampling is unsuitable as a noninvasive alternative to
neth S. Albert, Clinical Biopharmaceutics Research the collection of blood samples. Because of its inherent sensitivity, this
Unit, Upjohn Company, Kalamazoo, Michigan,
method promises to be a valuable tool in studying the bioavailability and
49001.
pharmacokinetics of ibuprofen in pediatric populations, when capillary
The work presented was based on the administra- sampling rather than venipuncture may be more convenient. It would also
tion of Motrin tablets, a registered trademark of the be valuable in multiple-dose studies in which extensive sampling may
Upjohn Manufacturing Company. limit the size of the blood specimen collected.

40 July 13, 1984 The American Journal of Medicine

 IBUPROFEN SYMPOSIUM-ALBERT and GERNAAT

FUNDAMENTAL PHARMACOKINETIC PROPERTIES

32
Ibuprofen is rapidly absorbed after oral administration,
E
......
with peak serum or plasma levels generally attained within CO>
..=,
one and a half to 2 hours. The drug is more than 99 per- Z
9 24
cent bound to plasma protein. An apparent linear dose-
response relationship exists between the amount of drug
...
!;;:
a:
z
w
u
administered and the area under the serum concentration z
c
u
time curve after single doses of 200 to 800 mg. Above 800 < 16
:E
mg, however, the area under the curve increases less S
than proportionately compared with increases in dose. ....
z
Ibuprofen is fully bioavailable when compared with an ~
~ 8
....:::>
oral control solution, with uniformity in bioavailability
!!!
among production lots. Confirmation of the uniformity in
bioavailability has been verified by testing 400- and 600-
mg tablets from each of three production lots. In addition, 4 6 8 10
the bioavailability of ibuprofen is only minimally altered by TIME AFTER DRUG ADMINISTRATION (HOURS)
the presence of food.
Eighty-four percent of an ibuprofen dose has been re- Figure 1. Capillary and venous plasma levels of ibuprofen
covered in the urine, primarily as conjugated hydroxy- and determined by a high-performance liquid chromatographic
carboxy-metabolites, with approximately 1 percent of a method with ultraviolet detection. Curves are virtually super-
imposable. Circles = capillary plasma; squares = venous
400-mg dose excreted unchanged. In normal volunteers,
plasma.
the hydroxy- and carboxy-metabolites do not appear in
the serum. The apparent serum half-life is approximately
two hours. The accumulation ratio of ibuprofen in serum is suggested that ibuprofen is highly bound to plasma pro-
about 1.2, consistent with its short half-life. tein and not extensively distributed.

DOSE-RELATED PHARMACOKINETICS

PHARMACOKINETIC MODEL A fundamental pharmacokinetic property of ibuprofen is

that the area under the total ibuprofen plasma concentra-
To elucidate the pharmacokinetic model for ibuprofen, tion curve increases less than proportionately to increases
individual subject concentration-time data from 15 normal in dose. To discover the cause of the observed nonlinear
volunteers were evaluated after ingestion of an ibuprofen pharmacokinetics, 15 volunteers were studied after four
oral solution [13]. Ibuprofen is best described by a two- oral doses of ibuprofen [14]. Each subject was assigned to
compartment open model, with first-order absorption one of three groups, and received one of four treatments
(Figure 2). This result was most interesting because both (A through D) sequentially over a four-week period. Treat-
arithmetic and geometriC mean data, based on average ments A, S, and C consisted of one, two, or three 400-mg
ibuprofen blood levels, indicated a one-compartment tablets of ibuprofen, respectively. Ibuprofen was adminis-
open model with two consecutive first-order input steps
rather than a two-compartment open model, based on
individual subject data. Therefore, it is apparent that indi-

D
vidual subject data, and not average data, are best used
to correctly elucidate a pharmacokinetic model.
This pharmacokinetic model has been applied to total
plasma concentrations after the administration of 400,
800, and 1,200 mg of ibuprofen in tablet form to young
volunteers [13]. On the basis of this analysis, absorption
of ibuprofen from tablets was not a simple first-order proc-
ess. Absorption profiles after ingestion of one tablet were
S-shaped, whereas those after two or three tablets had
Figure 2. A two-compartment open model for ibuprofen
partial linear segments, indicating zero-order absorption
pharmacokinetics based on individual subject concentra-
(Figure 3). Two relevant pharmacokinetic parameters ob- tion-time data. k12,k21 = intercompartmental rate constants;
tained from this two-compartment open model were half- ka = absorption rate constant; ke/ = elimination rate con-
life, which was 2.04 hours, and volume of distribution, stant. The half-life was 2.04 hours and the distribution vol-
which was 6.35 liters. The small volume of distribution ume of compartment one was 6.35 liters.

July 13, 1984 The American Journal of Medicine 41

IBUPROFEN SYMPOSIUM-ALBERT and GERNAAT

administered dose and the area under the total ibuprofen

plasma concentration time curve, as observed previously.
Figure 4 is a plot of the individual subject area under the
curve values versus the milligram per kilogram dose of
drug. The line drawn through the points is empirical and is
based on the least squares parabola forced through the
origin. Although this function should not be considered
predictive, particularly outside the dose range studied, it
does indicate the curvature in the data.
Figure 5 is a plot of the individual subject area under
the free ibuprofen plasma concentration time curve versus
the milligram per kilogram dose of drug. No curvature was
evident, suggesting a linear relation between free plasma
concentrations of ibuprofen and the dose administered.
Total urinary recovery of ibuprofen as unchanged drug
and its major metabolites was about 80 percent (range 76
to 85 percent) and consistent from treatment to treatment
[15]. This finding would indicate that urinary excretion of
ibuprofen and its metabolites is a linear function of dose,
and any dose dependency associated with the absorption
process is minor. Therefore, the disproportionate increase
in total plasma levels of ibuprofen may be due to nonlinear
protein binding of ibuprofen (Table I). Table I also summa-
rizes mean bound/free ratios of ibuprofen as a function of
TIME IN HOURS dose [14]. Mean ratios decrease significantly with increas-
ing dose, indicating that the binding of ibuprofen is nonlin-
Figure 3. Absorption profiles after ingestion of one, two, or
ear.
three 400-mg ibuprofen tablets. Each profile is that of a dif-
ferent individual, but it is representative of the subjects stud- PHARMACOKINETICS IN UNIQUE STUDY
ied. POPULATIONS

The Elderly. To determine if the same disproportionate

tered in accordance with a Latin square design over the area-dose relationship applies to the elderly, the phar-
first three weeks. In the final week of the study, all sub- macokinetics of ibuprofen were studied in 17 elderly sub-
jects received treatment 0, which was 20 ml of an oral jects [16] and compared with similar data from a previous
solution of ibuprofen (20 mg/ml). Plasma levels of both trial in 15 young volunteers [14]. Area-dose plots of total
total and free ibuprofen were measured for 12 hours, and drug concentrations exhibit curvature, whereas those for
urine was collected for 48 hours after drug administration. free drug show no evidence of curvature, suggesting a
In all subjects, there was a nonlinear relation between the linear relation between free plasma concentrations of

:; 400 • 2500
E •
.c E
.;, 300 ~ 2000
3 CO)
(.) c
:::I
;; 1500
<
ffi 200
:::I
<
•
u. Z
CI
....:::I
..: • ~
CI
1000
•
!! 100 ....
..:
..... § 500
~ w
CI w
I- ..:
u.
°0~---4~--~8----~12~--~16~~2'0 4 8 12 16 20
IBUPROFEN DOSE (mg/kg) IBUPROFEN DOSE (mg/kg)

Figure 4. Area versus dose relation for ibuprofen based on Figure 5. Area versus dose relationship for ibuprofen
total plasma levels. AUe = area under the curve. based on free plasma levels. AUe = area under the curve.

42 July 13,1984 The American Journal of Medicine

 IBUPROFEN SYMPOSIUM-ALBERT and GERNAAT

ibuprofen and the dose administered. These conclusions TABLE I Bound/Free Ratios (CalC,) of Ibuprofen As
are consistent with those in young subjects and indicate a Function of Dose"
that in the elderly, nonlinear total plasma concentrations Solution A B C
of ibuprofen are also due to nonlinear protein binding of Parameter =
(n 100) (n =102) (n =100) (n =104)
the drug. A thorough analysis of pharmacokinetic data in
the elderly is presented in this issue in the subsequent Mean 183 t 196H 173t 166t
Range 134-233 127-376 116-232 112.9-293.0
article by Gillespie and others. However, advanced age
Standard
has minimal influence on the pharmacokinetics of deviation 22.6 39.4 27.4 28.8
ibuprofen over a wide range of doses (400 to 1,200 mg CV(%) 12.3 20.1 15.8 17.4
given as a single dose), all of which are within the thera- 'Solution = 2Q-ml oral solution of 20 mglml of ibuprofen; A = one
peutic range for rheumatoid arthritis and osteoarthritis. 400-mg tablet; B = two 400-mg tablets; C = three 400-mg tablets.
Patients with Liver Disease. The pharmocokinetics of tMean values differ significantly (p < 0.05).
*Analysis of variance indicates that mean values differ significantly
ibuprofen in patients with alcoholic liver disease have also
(p < O.OOl).
been evaluated and compared with those obtained with
sulindac [17]. Fifteen patients with alcoholic liver disease
and 29 normal subjects were evaluated after the adminis-
tration of a single oral dose of 400 mg of ibuprofen or 200
mg of sulindac. Participants were designated as having poor hepatic function, this was probably an artifact. Statis-
normal, fair, or poor hepatic function depending on indo- tically significant differences in half-life were observed
cyanine green half-life. between groups with fair and with poor hepatic function;
Ibuprofen and sulindac pharmacokinetic parameters for however, relative to normal values, these differences
the three groups are shown in Table II. The maximal con- were not significant. On the basis of such findings, the
centration of ibuprofen in the alcoholic liver disease effects of alcoholic liver disease on the pharmacokinetics
groups was slightly depressed, although the difference of ibuprofen should be considered minimal despite the
was not statistically significant when compared with that of drug's extensive metabolism by the liver.
normal subjects. Absorption of the drug was slightly de- Several differences, however, in sulindac pharmacoki-
layed in some patients with poor hepatic function, but netic parameters were observed between the two alco-
again the difference was not statistically significant. Val- holic liver disease groups and normal subjects (Table II).
ues for area under the curve were significantly lower in Sulindac is metabolized to an inactive sulfone metabolite
patients with fair hepatic function than in normal volun- as well as reversibly metabolized to an active sulfide me-
teers. However, because no statistically significant differ- tabolite. Absorption of the parent compound was delayed
ences existed between normal subjects and those with in groups with both fair and poor hepatic function; maximal

TABLE II Kinetic Parameters (mean ± standard deviation) of Ibuprofen and Sulindac in Normal Subjects and
Patients with Fair and Poor Hepatic Function

Patients with Patients with

Normal Subjects Fair Hepatic Function (FHF) Poor Hepatic Function (PHF)
Drug =
(n 29) (n 9)= (n 6)= P =0.05
Ibuprofen
Cm... 27.9 ± 7.6 22.0 ± 4.4 21.1 :!: 5.4 None
T max 1.9 ± 1.4 1.5 ± 0.7 2.6 ± 2.2 None
AUG 103.0 ± 26.1 79.2:!: 20.8 100.0 ± 36.3 FHF-NML
t"2 2.2 ± 0.4 1.9 :!: 0.3 2.6 ± 0.6 FHF-PHF
Sulindac
Gmax 2.2 ± 0.9 5.0 ± 3.1 5.7:!: 1.5 None
Tm .. 1.2 + 0.8 2.1 ± 1.5 2.5 ± 2.1 FHF-NML, PHF-NML
AUG 13.0:!: 6.3 12.6 ± 7.2 37.4 ± 17.5 FHF-PHF, PHF-NML
Sulindac sulfide
C m.. 2.2 ± 0.9 2.8 ± 2.5 2.4 ± 1.0 None
Tmax 1.7 ± 0.9 3.9 ± 2.2 7.2 ± 2.7 All
AUC 10.2 ± 6.9 18.0 ± 13.8 39.4 ± 29.5 All
Sulindac sulfone
Cm.. 3.5 ± 2.3 1.3 ± 0.5 1.0 ± 0.8 FHF-NML, PHF-NML
Tmax 2.0 ± 0.8 3.9 ± 2.1 14.2 ± 13.0 All
AUG 29.5 ± 21.8 14.6 ± 8.0 23.3:!: 19.6 None
Gm.. = maximal concentration (g/ml); T max = time to maximal concentration (hours) ; AUG = area under the curve (g-hour/ml); t"2 = half-life
(hours) .

July 13, 1984 The American Journal of Medicine 43

IBUPROFEN SYMPOSIUM-ALBERT and GERNAAT

50

e...... DAY 3
40
~
z
o
Ii
a::
30
~
Z
....wz
8 20

...o
zw

1'::)E 10 Figure 6. Mean total ibuprofen plasma

!!:!
and synovial fluid concentrations after the
administration of one 600-mg tablet of
ibuprofen three times a day to eight pa-
00 1 2 3 4 5 6 7 01234567 tients with rheumatoid arthritis. White
circles = plasma; black circles = syno-
TIME AFTER DRUG ADMINISTRATION (HOURS)
vial fluid.

plasma concentrations were reached at 2.5 and 2.1 hours, limited number of synovial fluid data points. However,
respectively, compared with 1.2 hours for normal control evaluation of individual subject data revealed that in each
subjects. The formation of sulindac sulfide and sulindac case the decline in plasma and synovial fluid levels was
sulfone (the active and inactive metabolites) took signifi- parallel, as seen from the average levels shown in Figure
cantly longer in both groups of patients with alcoholic liver 6. They strongly suggest that half-lives in both fluids are
disease than in normal subjects. The time of maximal con- comparable. Further support for this premise comes from
centration of the metabolites also differed significantly the accumulation ratios in each fluid , calculated as the
between the groups with fair and poor hepatic function . ratio of the seven-hour concentration on day three to the
The area under the sulindac sulfide plasma concentration seven-hour concentration on day one. The ratios for
curve differed in all pairwise combinations of the groups, plasma and synovial fluid were 1.24 and 1.20, respec-
with the value for poor hepatic function being four times tively, as would be expected for a drug with a half-life of
that of the value for normal hepatic function. Therefore, about two hours.
the pharmacokinetics of sulindac, a pro-drug"
" that relies Synovial fluid/plasma concentration ratios, based on
on the liver for conversion to an active metabolite, appar- total and free drug at seven, nine, and 12 hours after peak
ently were markedly affected by alcoholic liver disease. In concentration , were greater than one, indicating a higher
contrast, alcoholic liver disease had little effect on concentration of drug in synovial fluid than in plasma. Ra-
ibuprofen pharmacokinetics. tios based on free drug were slightly higher than ratios
Patients with Rheumatoid Arthritis. Concentrations of based on total drug, probably because of lower albumin
ibuprofen in synovial fluid relative to concentrations in and total protein concentrations in synovial fluid than in
plasma were evaluated in eight patients with rheumatoid plasma.
arthritis [18]. Patients were given 600 mg of ibuprofen
three times a day for two days and on the morning of the
IBUPROFEN LEVELS IN OTHER BODY FLUIDS
third day. Serial plasma and synovial fluid specimens
were obtained simultaneously after the first and last Breast Milk. Breast milk and serum concentrations of
doses. Figure 6 shows the mean total ibuprofen plasma ibuprofen were measured in 12 patients after ingestion of
and synovial fluid concentrations on day one (after a sin- one 400-mg ibuprofen tablet every six hours for five
gle dose) and day three (at a steady state). doses, administered for relief of post-cesarean section
The half-life in plasma on day three averaged about two pain [19]. Serum concentrations of ibuprofen ranged from
hours, which agrees well with the half-lives in young vol- 15.8 ± 7.49 I-tg/ml at two hours to 1.3 ± 1.88 I-tg/ml at 34
unteers (2.3 hours), elderly volunteers (2.1 hours), and hours. The concentration of ibuprofen in breast milk was
patients with liver disease (2.3 hours). This finding indi- below detection levels (1 I-tg/ml) at all times. Estimation of
cates that the pharmacokinetics of ibuprofen, as judged the daily amount of breast milk produced suggests that
by the half-life, are consistent among populations with dif- the amount of ibuprofen to which a nursing infant would be
ferent characteristics. exposed is negligible, that is, less than 1 mg/day.
A definitive half-life for the disappearance of ibuprofen Saliva. As described previously, ibuprofen is not ex-
from synovial fluid could not be calculated because of the creted in saliva after ingestion of a single 400-mg tablet.

44 July 13, 1984 The American Journal of Medicine

 IBUPROFEN SYMPOSIUM-ALBERT and GERNAAT

clinical significance of the ibuprofen/aspirin interaction

60
has not been proved, the potential for an alteration in the
efficacy of these drugs does exist, and the use of aspirin
as an analgesic in patients stabilized on ibuprofen can be
50
questioned on pharmacokinetic grounds.
Acetaminophen. In contrast, it was recently reported
~ that the bioavailability and pharmacokinetics of ibuprofen
';;.40
!z are unaltered when given in combination with multiple
51 doses of acetaminophen, another commonly used over-
!C the-counter analgesic [20). In a drug interaction study in-
~ 30
~
volving 21 healthy adult volunteers, three treatments were
z
8 given in a crossover design: treatment A, 400 mg of
'" ibuprofen every six hours for eight doses; treatment B,
~ 20
...
S 650 mg of acetaminophen every six hours for eight doses;
treatment C, 400 mg of ibuprofen and 650 mg of aceta-
minophen given together every six hours for eight doses.
Serum samples were collected before each dose; after
dose eight, serial samples were collected for 12 hours.
The steady-state blood levels of acetaminophen and
ibuprofen were virtually superimposable when these
drugs were administered together. Because no drug inter-
Figure 7. Effect of aspirin on ibuprofen plasma levels. action was observed, acetaminophen can be considered
Black squares == ibuprofen + aspirin; black triangles = an appropriate over-the-counter analgesic in patients tak-
ibuprofen alone. ing ibuprofen. The pharmacokinetics of ibuprofen can
accurately be evaluated, even when acetaminophen has
been administered as a "rescue" measure. These results
are especially important in multiple-dose studies designed
to evaluate the pharmacokinetics of ibuprofen in patients
DRUG INTERACTIONS with rheumatoid arthritis or osteoarthritis.
Aspirin. One possible drug interaction involves the com-
CONCLUSIONS
bination of one nonsteroidal drug, ibuprofen, with the
over-the-counter use of another nonsteroidal drug, aspi- The nonlinear pharmacokinetics of ibuprofen can be ex-
rin. Single-dose bioavailability studies in normal volun- plained by nonlinear protein binding. The pharmacokinet-
teers have failed to show any effect of aspirin on ibuprofen ics of the drug are only minimally affected by advanced
blood levels. However, according to unpublished data, the age, the presence of alcoholic liver disease, or rheuma-
multiple-dose administration of 1,300 mg/day of aspirin toid arthritis. In addition, the drug can safely be combined
concomitantly with 2,400 mg/day of ibuprofen for five days with acetaminophen, although the concomitant use of
reduced ibuprofen plasma levels to less than half those aspirin can be questioned because the potential for re-
observed with ibuprofen alone (Figure 7). Although the duced efficacy does exist.

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July 13, 1984 The American Journal of Medicine 45

IBUPROFEN SYMPOSIUM-ALBERT and GERNAAT

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46 July 13,1984 The American Journal of MediCine