Multiple-Dose Acetaminophen Pharmacokinetics
CHANDRAHAS G.SAHAJWALLA** AND JAMESw. AYRES"
Received Februa 5, 1990, from the 'College of Pharmacy, Oregon State University, Cowallis, OR 97337-3507. Accepted for publication
December 6, 199r *Present address: International Drug Registration, Inc., 14915 Broschart Road, Rockville, MD 20850.
Abstract 0 Four different treatments of acetaminophen (Tylenol) were
administered in multiple doses to eight healthy volunteers. Each treat-
ment (325,650, 825, and 1000 mg) was administered five times at 6-h
intervals. Saliva acetaminophen concentration versus time profiles were
determined. Noncompartmental pharmacokinetic parameters were cal-
culated and compared to determine whether acetaminophen exhibited
linear or dose-dependentpharmacokinetics. For doses 5 18 mg/kg, area
under the curve (AUC), half-life (t,,*), mean residence time (MRT), and
ratio of AUC to dose for the first dose were compared with the last dose.
No statistically significant differences were observed in dose-corrected
AUC for the first or last dose among subjects or treatments. Half-livesand
MRT were not significantly different among treatments for the first or the
last dose. Statistically significant differences in t,,* and MRT were noted
(p ~0.05) among subjects for the last dose. A plot of AUC versus dose
for the first and the last doses exhibited a linear relationship. Dose-
corrected saliva concentration versus time curves for the treatments
were superimposable. Thus, acetaminophen exhibits linear pharmacok-
inetics for doses of 18 mg/kg or less. Plots of AUC versus dose for one
subject who received doses higher than 18 mg/kg were curved, sug-
gesting nonlinear behavior of acetaminophen in this subject.
Acetaminophen (paracetamol,N-acetyl paraminophenol) is
a widely used non-narcotic analgesic and antipyretic com-
pound. It is rapidly absorbed and distributed after oral
administration, with peak concentrations obtained within 40
to 60 min. Its pharmacokinetics after oral and iv administra-
tion can be best described by a two-compartment open model,
with a rapid distribution phase and a n elimination half-life of
2 to 3 h in the usual dose range.1-B Acetaminophen is
relatively uniformly distributed throughout most body tis-
sues and fluids in appreciable concentrations, reaching a
tissue-to-plasma concentration ratio of about unity, except in
fat and cerebrospinal fluid.9.10
Acetaminophen is incompletely available to systemic cir-
culation after oral administration, since it is partly metabo-
lized during absorption, primarily to pharmacologically in-
active products. Present studies suggest that -10% of ace-
taminophen is subject to this presystemic biotransformation
at doses of 1 g or more, and the percentage may be higher
(40%)at lower do~es.4~7.11~12About 25%of the acetaminophen
dose has been reported to be metabolized by a first-pass effect.5
The drug is extensively metabolized and excreted largely in
urine as various conjugates: 4 6 5 5 % as glucuronide conju-
gates, 2&30% as sulfate, and 1 5 5 5 %as cysteine and mer-
capturic acid conjugates. A minor fraction of acetaminophen
is converted by cytochrome P-450-dependent hepatic mixed
function oxidase to a highly reactive alkylating metabolite,
which is probably n-acetyl-p-benzoquinoneimine.13 This me-
tabolite is usually rapidly inactivated by conjugation with
reduced glutathione and excreted in urine as cysteine and
mercapturic acid conjugates. Overdoses of acetaminophen
cause acute hepatic necrosis due to saturation of conjugation
pathways, and glutathione stores become depleted due to
covalent binding of the excessive reactive metabolites (pos-
sibly an epoxide) to vital cell constituents.16J7
OOZZ-3549/97/0900-0855$01.00/0
0 7 99 7, American Pharmaceutical Association
Although acetaminophen is a relatively safe analgesic in
high doses and over prolonged periods, in overdose its me-
tabolism may produce a quantitatively minor metabolite of
drug which can destroy the enzyme systems responsible f o r its
reduction. This could paralyze the capacity of the liver to
reduce other toxic substances in addition to the drug itself.
Recently, Borin and Ayress conducted a study with 15
human subjects by administering five different single doses
(up to 2000 mg) of acetaminophen and collected sailiva
samples for 16 h post dosing. These authors concluded that
statistically significant differences in elimination rates and
dose-corrected area under the curve (AUC)found among doses
were suggestive of dose-dependent pharmacokinetics.
Multiple-dosing pharmacokinetics of acetaminophen have
not been well defined in the literature. Acetaminophen has
recently become available in a nonprescription sustained-
release dosage form (Drixoral Plus, Schering Corporation,
Bloomfield, NJ). If saturable presystemic biotransformcci t'ion
0ccurs,4~7JOJ1then extent of bioavailability ( F ) may be de-
creased for a sustained release of drug relative to immediate
release of the same dose. The effect may be confounded with
multiple dosing if dose-dependent variation in elimination
rate occurs.8
One study of multiple rectal administration has been
reported18 in which acetaminophen (300 mg) and salicyla-
mide (200 mg) in combined repetitive (three times, every 4 h)
administration of suppositories was studied in 10 male vol-
unteers. This study concluded that acetaminophen pharma-
cokinetic behavior conformed to literature values for a single
dose and was described by a two-compartment open model.
The kinetics of acetaminophen following single- and double-
strength administration to febrile children19 have been $stud-
ied and found to be linear, but no multiple-dose study with
increasing doses has been conducted in adults. The objective
of this study was to determine whether acetaminophen
exhibits dose-dependent pharmacokinetics when comparing
single dose data with steady-state data when the maximum
dose is that recommended by FDA. If dose dependency exists,
there should be nonlinear accumulation of drug at steady
state.
Experimental Section
Study Design-Eight healthy volunteers rage 22 to 29 years! were
administered four different treatments (325, 650, 825. or 1000 rng of
acetaminophen as Tylenol). Each treatment was administered orally
in fivemultipledoses with dosingintervalsof6 h each. Saliva samples
were collected for 36 h after administration of the first dose. Each
participant signed an informed written consent.
Treatments were administered to each subject every 6 h at 0 . 6 , 12,
18, and 24 h in the following manner: ( A , 325-mg Tylenol table:s 11ot
no. AFR318 12/87; McNeil, Fort Washington, PA,; [ B I 650 .ng of
Tylenol (two 325-mg tablets); tC) 825 mg of Tylenol tone e ~ c hof
325-mg and 500-mgTyleno1 Extra Strength tablets; lot no. AI)GF9d6
5/86); (D)1000 mg of Tylenol (two 500-mg extra strenbqh tatdetsi.
Treatments were administered on four separate occasions separated
by at least a week according to a randomized block design. Su'zjects
fasted at least 12 h prior and 1 h after the first dose in each Fhase.
Journal of Pharmaceutical Sciences / 855
Vol. 80, No. 9, September 1991
 Subjects were also required to fast 2 h prior to and 1h after each dose
for subsequent doses during each phase. No alcohol was permitted
during the study. Treatments were taken with 6 fluid ounces of water
and, immediately after swallowing the tablets and fluid, the mouth
was rinsed with 20 mL of commercial mouthwash (containing 0.045%
cetylpyridium chloride and 0.005% domiphen bromide as active
ingredients) followed by a water rinse to remove drug that was
adsorbed to the buccal mucosa. Saliva samples were collected by
chewing squares of parafilm (1 inch x 1 inch; American Can
Company, Greenwich, CT) for 1 min with continuous spitting into a
12-mL glass centrifuge tube. All subjects were provided with an
alarm watch to remind them of sample and dose times.
Saliva was centrifuged (Beckman model TJ-6 centrifuge, Palo Alto,
CA) a t 3000 rpm for 30 min to remove mucous and particulate matter.
Salivary supernatant was transferred to a polypropylene container
with a lock cap and frozen a t -20 "C until analyzed.
All participants in the study were taking no other medication
during and 1 week prior to each phase. Criterion for exclusion from
the study included history of chronic disease, therapy with an
enzyme-inducing agent within the previous 30 days of the study,
recent myocardial infarction, allergy to acetaminophen, and subjects
with bleeding gums.
Standard Solutions-Stock solutions containing 20-1000 mg/mL
of acetaminophen (USP reference standard; USP, Inc., Rockville, MD)
were prepared in distilled, deionized water. "he internal standard
was 2-acetaminodophenol (Aldrich Chemical, Milwaukee, WI) in
deionized water (60 pg/mL).Standards were prepared by spiking 500
pL of blank saliva with 25 pL of stock solutions. Then, 100 pL of the
standard or unknown was combined with 100 pL of internal standard
in 250-pL polyethylene centrifuge tubes and vortexed for 15 s.
High-Performance Liquid Chromatography Assay-Analysis of
saliva samples was carried out using the HPLC method reported by
Borin and Ay-res.8 Linearity of peak height ratio versus acetami-
nophen concentration was excellent, with correlation coefficients of
>0.995 and coefficients of variation ranging from 1 to 3%.
Noncompartmental Analysis-Noncompartmental pharmacoki-
netic parameters for first and last dose were calculated and compared
to determine whether acetaminophen exhibited linear or dose-
dependent pharmacokinetics. Half-lives &*) were calculated using
least square regression of the slopes of the terminal phase of
acetaminophen concentrations versus time curves.
Analyses by ANOVA were performed using SIPS (Statistical
Interactive Programming System for Cyber 70173,Department of
Statistics, Oregon State University) for statistical analysis for dose-
corrected AUC, t1,2rterminal slopes, and mean residence times (MRT)
among treatments and subjects. For regression analysis, BMDP was
used (Statistical Software, Inc., Version 1988 VAXNMS, Los Ange-
les, CA). Daily secretion of saliva normally ranges between -800 and
1500 mL.20 Hence, <1% of the dose would be recirculated due to
swallowing of saliva containing drug. This amount was ignored in all
pharmacokinetic analyses.
Pharmacokinetic parameters were calculated for the first dose, fifth
dose (assuming steady state), corrected fifth dose (assuming steady
state not reached), and fourth dose. Area under the curve (AUC) and
area for the first moment (AUMC) were calculated using the trape-
zoidal rule.21.22 The AUC and AUMC for the first dose (0-6 h) were
extrapolated to infinity, whereas for the steady-state (24-30 h) saliva
acetaminophen concentrations, areas were not extrapolated to infin-
ity (assuming steady state has been reached by 24 h). Area under the
curve and other pharmacokinetic parameters were calculated for
fourth dose (18-24 h) in a similar fashion as for steady state. The AUC
and AUMC for the fifth dose were recalculated (corrected parameters
for fifth dose) assuming that steady state may not have been reached.
This correction was achieved by extrapolating the terminal monoex-
ponential decline in saliva acetaminophen concentrations of the
fourth dose to 30 h, and subtracting these from observed fifth dose
concentrations, since saliva acetaminophen concentrations for the
fifth dose include residual concentrations produced by previous doses.
The AUC and AUMC were calculated from corrected 24-30-h data
extrapolated to infinity. The ratio of AUMC to AUC gave the MRT.22
Note that drug concentration in saliva is reported to be virtually
equivalent to drug concentration in serum,=25 which allows use of
saliva drug concentration versus time data to calculate MRT and
other pharmacokinetic parameters as discussed below.
Clearance is a function of intrinsic ability of certain organs, such
as the liver and kidney, to metabolize or excrete a drug and blood flow
rates to these organs. As amount of drug eliminated after iv
administration would equal the dose given, clearance (CL) is calcu-
lated as iv dose/AUC. Complete bioavailability is not assured when
drug is given orally, hence the ratio of dose to AUC is termed apparent
clearance (CL,,,).27
Since the doses in this research were administered orally, the
apparent volume of distribution at steady state (Vd,) was calculated
as CL,,, * MRT. Absolute bioavailability could not be calculated.
However, bioavailability relative to the 1000-mg dose was calculated
as the ratio of the average AUC for each dose to the average AUC for
the 1000-mg dose.
Results and Discussion
All subjects complied with the protocol and completed the
study. Three subjects reported having a headache a few hours
after the last dose. They did not report a headache after each
treatment and there was no association between the dose and
the reported headache. Two subjects reported headache at the
lower dose, whereas the third subject was at a higher dose.
One subject was female and the other two were males. This
side-effectcould be attributed to a disturbed sleep pattern due
to the fact that subjects had to waken many times during the
night to collect samples.
First Dose Versus Steady State-Mean saliva acetami-
nophen concentrations have been reported to be proportional
and virtually equivalent to serum concentrations.23-~.28.29
Mean saliva acetaminophen concentrations versus time
curves for all four treatments (325,650,825,and 1000 mg', are
presented in Figure 1.Peak acetaminophen concentration for
the first dose and the last dose (steady state) were reached
within 30 to 60 min, respectively, indicating rapid absorption
and distribution.
Mean pharmacokinetic parameters are presented in Tables
I and I1 (first and fifth dose). Dose dependency could be
established if there is a significant change among treatments
or between the first and the last dose (due to nonlinear
accumulation of drug on multiple dosing) for t,,,, dose-
corrected AUC, or MRT, or if the plot of AUC versus dose is
nonlinear. Analysis of dose-corrected AUC by ANOVA indi-
cated no significant differences among treatments (p <0.05)
for the first dose or the last dose. Also, no statistically
significant differences were noted among treatments for
10.00
1.00
'.a0 4.00 6-00 12.00 16002d.w 24.00 26.00 32-00 3d.00
TIWE (HOURS)
Flgure 1-Mean saliva acetaminophen concentration versus time curve
for eight human subjects following multiple oral administration of com-
mercial acetaminophen tablets at 0,6,12,18, and 24 h. Key: (0)325 mg;
(A) 650 mg; (*) 825 mg; (0)1000 mg.

856 / Journal of Pharmaceutical Sciences

Vol. 80,No. 9, September 7997
Table I-Mean Pharmacokinetic Parameters for the First DoM)' following Oral Adminlstratlon of Acetaminophen in Yultlple Dosing to
Eight Subjects
Dose, mg p, h-lb tin, hC MRT,
h
AUC,
~ 1 *9h/mL
AUC/D,
mg * h/mL * mgd
Relative
Bioavailabilitye
tP muma'
cL,ppp
~ ~~~~

325 0.375 1.85 2.45 18.99 0.058 0.79 0.75 5.40 389.4
(0.075) (0.061) (4.94) (0.0152) (0.44) (1.24) (95.8)
650 0.381 1.82 2.47 35.31 0.054 0.91 0.44 14.91 323.1
(0.078) (0.28) (6.75) (0.010) (0.120) (3.10) (48.8)
825 0.335 2.07 2.57 49.12 0.060 0.94 0.50 15.28 328.1
(0.073) (0.31) (8.32) (0.010) (0.23) (5.00) (84.0)
1000 0.315 2.20 3.16 59.27 0.059 1.oo 0.59 19.14 306.5
(0.043) (1.07) (10.81) (0.011) (0.27) (3.75) (82.4)
a First doses from 0 to 6 h; values in parentheses are standard deviations. Slope of the terminal portion of the saliva acetaminophen
concentration-time curves. 0.693/p.'Area under the curve divided by dose (0). Relative bioavailabilily is calculated as bioavailabilityfor each dose
relative to the 1000-mg dose; average AUC for a dosdaverage AUC for 1000-mg dose. 'Apparent clearance = dose/AUC. gTime to peak
concentration.

Table 11-Mean Pharmacoklnetlc Parameters for Steady State' followlng Oral Admlnlstratlon ol Acetaminophen In Muitipb Oorlng to
Elght Subjects

325 0.364 1.90 2.81 14.70 0.0452 0.99 0.50 7.48 300.4 0.846
(0.369) (0.68) (3.83) (0.012) (0.23) (1.31) (68.07)
650 0.369 1.88 2.93 34.20 0.053 0.93 0.72 13.59 316.6 0.953
(0.056) (0.52) (5.16) (0.008) (0.31) (1 . w (58.80)
825 0.338 2.05 3.13 44.89 0.054 1.01 1.06 16.74 287.2 0.864
(0.047) (0.47) (13.73) (0.017) (0.68) (4.12) (49.05)
1000 0.314 2.21 3.36 58.81 0.059 1 .oo 0.97 18.10 291.4 0.941
(0.043) (0.49) (19.30) (0.019) (0.67) (4.24) (64.7)
a Steady-state doses from 24 to 30 h; values in parentheses are standard deviations. Slope of the terminal portion of the saliva acetaminophen
concentration-time curves. 0.693/p. Area under the curve divided by dose (0). Relative bioavailability is calculated as bioavailabilityfor each dose
relative to the 1000-mg dose; average AUC for a doselaverage AUC for 1000-mg dose. 'Apparent clearance = dose/AUC. BTime to peak
concentration. Steady-state volume of distribution (Vd,) = CL,, .MRT.

MRT21 (suggesting linearity of kinetics) or terminal slopes 100-

and tlIzfor the first or last doses. However, the average tllafor
the first dose ranged Erom 1.85 (lower doses) to 2.2 h (for
80 -
higher doses), but did not increase significantly at steady
state compared with the first dose for a particular treatment.
-
-I
0

Plots of mean AUC versus dose for the first and the fiRh doses
are presented in Figure 2, which does not exhibit any
5cn 60-
curvature. Area under the saliva concentration versus time 3
v

curve increases proportionately with dose, indicating linear- 0 40-

3
ity of pharmacokinetics. Area under the curve versus dose in a
mgkg body weight is presented in Figure 3. Data points for 20 -
doses >18 mg/kg (one subject only) were excluded since
inclusion of said data results in a high negative intercept for
04 1

100- 0 4 8 12 16 20
DOSE I WT (mg/kg)
80 - Flgure %Area under the acetaminophen concentration-time curve
s' versus dose in mg/kg body weight. Key: (0)first dose; (0)steady-state
E T dose.
60-
0
5
v

o 40- the first dose data. First-dose data are described by y = 3.31~
3
Q
- 1.025,and steady-state data are described by y = 3.17~+
0.83, as determined by linear regression. There was no
20 - improvement in fit using polynomial regression. Slopes were
1 compared for first-dose and steady-state data and were not
04
found to be statistically Significantlydifferent a t the 0.05level
0 400 800 1200
of significance. The data euggeet that acetaminophen follows
'linear kinetics with multiple doses up to 1000mg or doses <18
DOSE (mg) mgkg bqdy weight. The significant differences noted in tl,z
Figure 2-Mean area under the saliva acetaminophen concentration- and MRT among subjecta were expected due to intersubject
time curve versus dose for eight subjects. Key: (0)first dose; (0) biological variation.
steady-state dose. The maximum drug concentration in saliva),C( among

Journal of Pharmaceutical Sciences / 857

Vol. 80, No. 9, September 1991
treatments increased with increasing dose, as would be
expected. The time to reach C,,, (tmax) for the first dose
ranged from 0.44to 0.70 h, and that at steady state ranged
from 0.50 to 1.06 h. Although statistically not significant,
mean t,, for the fifth dose (650,825, and 1000 mg) was longer
than that for the first dose, suggesting that the rate of
absorption (K,)may be dose dependent. The K, could not be
calculated as there were not enough data points prior to peak
concentration of the drug. Dose dependency of absorption has
also been suggested by other researchers.4.7
Saliva acetaminophen concentrations for individual sub-
jects were normalized and dose corrected to 325 mg. Average
dose-corrected concentration versus time curves are pre-
sented in Figure 4 and are superimposable, indicating linear
pharmacokinetic behavior of acetaminophen. Acetaminophen
is reported to follow two-compartment model pharmacokinet-
ics.2 Since sufficient data were not available to determine K,
and other microconstants reliably, noncompartmental anal-
ysis was preferred to compartmental analysis. Estimation of
K, during multiple dosing is difficult since residual drug from
the previous dose superimposes on doses that follow. Residual
concentrations of previous doses were subtracted from the
fdth dose (corrected fifth dose; presented later in this section),
but still there were not enough points prior to peak concen-
trations to calculate K, reliably. Also, K, was not calculated
from MRT as the model cannot be well defined23 for this saliva
data. A longer t,, for higher doses at steady state (Table 11)
may suggest dose-dependent absorption, possibly due to a
decreased rate of dissolution with increasing dose.
It has been reported that with some drugs, drug-induced
malabsorption syndrome can alter the percentage of drug
absorbed, decreasing the bioavailability after administration
of repeated doses due to a decrease in F (fraction of the dose
absorbed) or due to an increase in the total body clearance
(AUC = FD/CL). Rawlins et al.4 reported that acetaminophen
bioavailability decreases from 0.9 at 1000 and 2000 mg to 0.63
at 500 mg for oral doses. This has been attributed to presys-
temic biotransformation or metabolism in the epithelium of
the GI tract or a combination of such processes.7 The AUC at
steady state for some subjects was lower than the AUC for the
first dose. This observation of decreased AUC at steady state
I
100.00
3
9
-
G
10.00
Figure 44Saliva acetaminophen concentration versus time curve for
eight human subjects normalized to the 325-mg dose following multiple
oral administration of commercial acetaminophen tablets at 0, 6, 12, 18,
and 24 h. Key: (0)325 mg; (A) 650 mg; (*) 825 mg; (0)1000 mg.
858 I Journal of Pharmaceutical Sciences
Vol. 80, No. 9, September 1991
could be attributed to presystemic biotransformation or drug-
induced malabsorption syndrome. Bioavailability relative to
the 1000 mg dose was calculated and is presented in Tables I
and 11. Relative bioavailability for the first dose of 325 mg was
-80% versus 91 and 94% for 650- and 825-mg doses, respec-
tively. Bioavailability relative to the 1000-mgdose at steady
state was 93-99% for all treatments, indicating that at steady
state, the amount of drug absorbed from lower doses (325 mg)
is not substantially different from that absorbed from higher
doses (650-1000 mg). However, for the first dose, relative
bioavailability from the lower dose (325 mg) was considerably
lower (20%)than that from the higher dose (1000 mg); this is
in agreement with reports by Rawlins4 et al. and Borin and
Ayres.8 It should be noted that Rawlins et al. calculated
absolute bioavailability.
Apparent clearance (dose/AUC; Table I and II), although
not significantly different, decreases as the dose is increased.
Apparent clearance also decreases at steady state compared
with the first dose. Decreased relative bioavailability based
on AUC for 325 mg (first dose) could be attributed to increased
apparent total body clearance. Total body clearance reported
by Rawlins et al.4 is 352 2 40 mu min and is close to the
calculated CLapp(Tables I and 11).
Steady-state apparent volumes of distribution (Vd,,), cal-
culated as CLapp* MRT, are presented in Table 11. Apparent
Vd,, ranged from 0.84 to 0.95 Lkg, indicating that apparent
Vd,, is independent of dose (maximum difference in apparent
-
Vd,, among treatments was 12%).The V d , values reported
for 1000-mg injections and 12-mgkg injections are 0.9 and
0.96 Lkg, respectively.30J2
Dose-normalized plots for all subjects except subject No. 2
were superimposable (Figure 4). Figure 5 indicates that
nonlinear pharmacokinetics were followed in subject No. 2.
Subject 2 received a maximum of 18.18 mg/kg body weight
dose (1000 mg), whereas all other subjects received doses
lower than 18 mgkg. This indicates that acetaminophen may
follow nonlinear kinetics for doses >18 mg/kg; however, this
cannot be substantiated until an organized study adminis-
tering doses > l 8 mgkg is conducted. A study conducted with
children,lg in which multiple doses of 24 to 30 mgkg were
administered every 8 h for 72 h, did not indicate nonlinear
pharmacokinetics for acetaminophen. A single-dose study8
suggests that nonlinearity occurs a t doses above -20 mgkg.
Fifth Dose Corrected-In calculations of the above-
discussed parameters, steady state was assumed, and AUC
and AUMC were calculated without extrapolating to infinity
for the fifth dose. The AUC and AUMC for the fifth dose were
recalculated (corrected fifth dose; as explained in the Exper-
'O01
- 8o 1
0 1 I
0 400 800 1200
DOSE (mg)
Figure &Area under the saliva acetaminophen concentration-time
curve versus dose for subject No. 2. Key: (e)first dose; (0)steady-state
dose.
Table Ill-Mean Pharmacoklnetlc Parameters for the Fifth Dose' (Corrected for Residual Concentrations of Prevlous Doses) following
Oral Admlnlstratlon of Acetamlnophen In Multiple Doses
AUCID,
Dose, mg p, h-lb tim h" MRT, h AUC, pg . h/mLd mg . hImL mge C L ,mUmin'
325 0.335 1.952 3.24 19.03 0.059 311.6
(0.072) (0.99) (6.54) (0.020) (93.2)
650 0.399 1.737 2.83 32.62 0.050 351.7
(0.084) (0.42) (8.89) (0.014) (85.4)
825 0.346 2.003 3.41 45.66 0.055 314.9
(0.042) (0.51) (9.15) (0.011) (79.6)
1000 0.356 1.950 3.75 615 7 0.062 288.1
(0.043) (0.79) (18.42) (0.016) (68.9)
a Values in parentheses are standard deviations. Slope of the terminal portion of the saliva acetaminophen concentration-lime curves. '0.693lp.
Area under the curve divided by dose (0). Relative bioavailability is calculated as bioavailability for each dose relative to the 1000-mgdose; average
AUC for a doselaverage AUC for 1000-mg dose. 'Apparent clearance = dose/AUC.

Table IV-Mean Pharmacoklnetlc Parameters for the Fourth Dose' following Oral Admlnlstratlon of AcetamlnoDhen In MultlDle Doses
AUCID,
Dose, mg p, h-lb 4/29 hC MRT, h AUC, pg h/mLd -
mg h/mL. mge CL,,,, mumin'

325 0.341 2.032 2.33 20.09 0.062 295.8

(0.108) (0.160) (6.48) (0.021) (95.1)
650 0.325 2.132 2.32 35.75 0.055 316.4
(0.1 14) (0.215) (8.19) (0.0126) (67.7)
825 0.299 2.318 2.46 47.87 0.058 301.4
(0.079) (0.289) (12.01) (0.015) (66.1)
1000 0.321 1.159 2.35 60.96 0.061 292.0
(0.069) (0.155) (15.60) (0.016) (66.1)
a Fourth doses from 16 to 24 h; values in parentheses are standard deviations. Slope of the terminal portion of the saliva acetaminophen
concentration-lime curves. " 0.693Ip. Area under the curve divided by dose (0). Relative bioavailability is calculated as bioavailability for each dose
relative to the 1000-mg dose; average AUC for a dose/average AUC for 1000-mgdose. 'Apparent clearance = dose/AUC.

imental Section) assuming that steady state may not have
been reached; these pharmacokinetic parameters are pre-
sented in Table 111. As expected, dose-corrected AUC, MRT,
CLapp,and tIl2were not significantly different among treat-
ments or compared with parameters calculated assuming
steady state was reached by the fifth dose.
Fourth Dose-Mean pharmacokinetic parameters calcu-
lated for the fourth dose (1Eb24 h) for individual subjects are
presented in Table IV. Steady state was assumed while
calculating these parameters. No significant differences were
noted in dose-correctedAUC, CL, ,or tl,2 among treatments.
The MRT values for 325,650, or 8% mg were not significantly
different from that of steady-state MRT (Table 11). However,
MRT for the fourth dose for 1000 mg was significantly
different from that at steady state. Half-lives for the fourth
dose were slightly higher than those at steady state, although
the terminal slopes (p)were not significantly different among
treatments. Parameters for the fourth dose may not be
reliable as there were only six data points during the dosing
interval; this could give incorrect estimates of AUC and
terminal slopes.
Conclusions
All subjects followed the protocol and completed the study
successfully. Peak concentrations for all treatments were
reached within 1h, indicating rapid absorption and distribu-
tion. The t,,, although statistically nonsignificant, tended to
increase at higher doses at steady state. The C, was
significantly different for treatments, as would be expected
with increasing doses. Dose-corrected AUC, MRT, tIl2,and
CL,, were not significantly different among treatments.
Plots of saliva acetaminophen concentrations normalized to a
325-mg dose, versus time, were superimposable, indicating
linearity of kinetics (for doses <18 mgIkg). Based on peak and
trough levels and comparing first-dose and steady-state pa-
rameters, no nonlinear accumulation of drug was noted over
the study period of treatments. This is in agreement with the
results of Nahata and Powell19 who reported no nonlinear
accumulation of drug in children receiving 24-30-mgkg
doses every 8 h for a period of 72 h. Plots of mean AUC versus
dose and AUC versus dose in mgkg body weight were linear,
and slopes of linear regression fitted lines for first and last
doses were not significantly different at the 0.05 level of
significance. However, one subject, who received >18 mgkg,
exhibited nonlinear kinetics based on a curved plot for AUC
versus dose. Although acetaminophen m a y follow (in adults)
nonlinear dose-dependent kinetics8 for doses >18 mgkg, it is
possible that this one subject had impaired metabolism of the
drug compared with other subjects (liver function tests were
not carried out for any of the subjects participating in the
study). However, nonlinearity cannot be substantiated until
an organized study administering doses >18 mgkg is con-
ducted.
Bioavailability relative to the 1000-mgdose at steady state
was comparable for high and low doses. However, for the first
dose, the 325-mg dose was only 80% bioavailable compared
with the 1000-mgfirst dose. This result and the fact that t,,
increases with dose support the finding of Rawlins et al.4 and
Borin and Ayress that lower doses had lower bioavailability
for single doses. However, in multiple dosing when steady
state is reached, bioavailability is comparable for the doses
studied.
References and Notes
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Clin. Pharmacol. Ther. 1978,24, 420-431.

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