British Journal of Anaesthesia 85 (4): 512-9 (2000)

Pharmacokinetics of rectal paracetamol after repeated dosing in

children
T. w. Hahn l *, s. w. Henneberg'', R. J. Holm-Knudserr', K. Erikserr', s. N. Rasmusserr' and
M. Rasmussen'

'Departmeni of Pharmaceutics and 3Department of Pharmacology, The Royal Danish School of Pharmacy,
Universitetsparken 2, DK-2100 Copenhagen, Denmark. 2Department of Anaesthesiology, Copenhagen
University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
*Corresponding author

Twenty-three children (aged between 9 weeks and II yr) were given paracetamol suppositor-
ies 25 mg kg-I every 6 h (maximum 5 days) after major surgery and serum and saliva concentra-
tions were measured. There was a good correlation (r=0.91, P<0.05) between saliva and serum
concentrations. A one-compartment linear model with first-order elimination and absorption
and lag-time was fitted to the data (ADAPT II). At steady state, the mean (SD) concentration
was 15.2 (6.8) mg litre-I. Mean (SD) time to reach 90% of the steady state concentration was
I 1.4 (8.6) h. Body weight, age and body surface area were well correlated (P<0.05) with clear-
ance and apparent volume of distribution. There was no evidence of accumulation leading to
supratherapeutic concentrations during this dosing schedule for a mean of approximately 2-3
days.

BrJAnaesth 2000; 85: 512-9

Keywords: analgesics non-opioid, paracetamol; children; pharmacokinetics, paracetamol
Accepted for publication: March 8. 2000

Paracetamol has gained wide acceptance as a simple and Methods

safe antipyretic and analgesic in children. When oral
administration is impractical, paracetamol is frequently
given rectally. The administration of paracetamol to chil-
dren is most commonly based on body weight.' Based on a
computer simulation, it has been suggested that a rectal
loading dose of 50 mg kg-1 followed by 30 mg kg-1 every 6 h
should be the preferred regimen in children. 2 Several single
dose studies have been carried out to investigate the
pharmacokinetics of rectal paracetamol in children. 3- 13
However, there is very limited clinical knowledge about the
pharmacokinetics after repeated therapeutic doses in chil-
dren.!" partly as a result of blood sampling limitations and
ethical considerations.
Paracetamol has been found to pass readily from blood to
saliva via the salivary glands resulting in similar concen-
trations in adult volunteers'< and patients. 16
The purpose of this study was to confirm the correlation
between serum and saliva concentrations and to investigate
the pharmacokinetics of paracetamol after repeated rectal
administration of 25 mg kg- 1 every 6 h for 5 days in
children.
Patients and protocol
Twenty-three children (ASA physical status I-II, aged
between 9 weeks and 11 yr), scheduled for surgery with an
anticipated need for analgesia for several days postopera-
tively were studied. The study protocol was approved by the
regional Ethics Committee and the Danish Medicines
Agency. Verbal and written information was given, and
written informed consent was obtained from the parents.
The children provided verbal assent to participate when
possible and were excluded if they had received para-
cetamol 24 h prior to the time of surgery, had a history of
liver disease, or paracetamol intolerance.
Anaesthesia was induced intravenously or with an
inhalational agent and nitrous oxide/oxygen. Post-
operatively, some children were given epidural bupiva-
caine/fentanyl and others had i.v. morphine either as patient
controlled analgesia (PCA) or on a 'as required' basis. After
induction of anaesthesia, the first dose of paracetamol 25 mg
kg- 1 was given. One or two of the five available suppository
doses (50, 125,250,500, 1000 mg) were used to administer

© The Board of Management and Trustees of the British Journal of Anaesthesia 2000
 Pharmacokinetics of recta! paracetamo!
a dose as close as possible to 25 mg kg- l for each child.
Subsequent doses of paracetamol 25 mg kg-I were given at
approximately 6 hourly intervals for up to 5 days post-
operatively.
Saliva and blood samples were obtained immediately
before insertion of suppositories and at 1, 2, 3 and 4 h after
the administration of the first dose. On the following days,
blood and/or saliva samples were taken before administra-
tion of the morning dose and at 1, 2, 3 and 4 h after these
morning doses. Paracetamol was administered for up to 5
days. Blood samples were drawn from a central venous
catheter or a peripheral vein. Saliva samples were obtained
using the Salivette citrus device (Sarstedt Laboratories,
Niimbrecht, Germany) developed especially for saliva
sampling. The Salivette citrus consists of a cotton wool
swab (containing 25 mg citric acid to stimulate saliva
production), which is placed in the oral cavity for 2-3 min. 17
A string was attached to the swab to avoid accidental
swallowing. Binding of paracetamol to the swab was
investigated prior to this study and was found to be a
maximum of 2% when compared with saliva samples
collected by spitting. Citric acid did not interfere with the
analysis and stimulation of saliva production and had no
influence on the concentration of paracetamol in saliva. IS
The exact dose and time of administration was noted along
with the time of collection of blood and saliva samples.
Analysis of samples
Saliva samples were kept refrigerated at 4°C for a maximum
I h until the saliva was centrifuged out of the swab. Blood
samples were allowed to clot for I h before serum was
separated by centrifugation. Immediately after centrifuga-
tion, saliva and serum samples were frozen at -20°C until
assayed. Saliva and serum samples were stable at -20°C for
at least 6 months. After thawing, 60 ~I of sample was mixed
with 120 ~I of a protein precipitating solution (2%
ZnS04.7H20 in I: 1 methanol/water) containing the internal
standard (metacetamol, 6 mg litre.") and whirl-mixed for 30
s before centrifugation at 10 000 g for 10 min.
Paracetamol concentration was determined by high
performance liquid chromatography (HPLC). The HPLC
system consisted of a Merck Hitachi automatic integrated
system with a L-7100 pump, L-7400 UV-detector, L-7200
autosampler and a D-7500 integrator. A Spherisorb RP-18
(250X4.6 mm, 5 urn) column and a LiChrospher 100 RP-18
(5 urn) pre-column were used. The chromatographic
conditions were as follows: wavelength 248 nm, mobile
phase flow 1 ml min-I, the mobile phase consisted of
acetonitrile-o.l M sodium acetate pH=4 (20:80 v/v).
Triethylamine 150 ~I was added per litre of mobile phase.
The injection volume was 20 ul. Standard curves were
linear in the range 0-40 mg litre-I. The intra day coefficient
of variation was 6.7% at 0.05 mg litre-I and 0.4% at 40 mg
litre-I. The between-day coefficient of variation was 0.8-
2.2% when concentrations ranged from 1-40 mg litre'":
513
Statistics and pharmacokinetic modelling
Data are presented as mean values with SD, median and
ranges as appropriate. Pearson's correlation was used for
analysis of saliva-serum correlations and to evaluate the
influence of demographic data on pharmacokinetic param-
eters. Statistical significance was defined as P<0.05.
Pharmacokinetic modelling was performed using the
computer program ADAPT II, release three (D.Z. D'argenio
and A. Schumitzky, University of Southern California,
USA, 1992).
A one-compartment linear model with first-order elimin-
ation and absorption and lag-time was fitted to the data. The
goodness of fit was evaluated by visual inspection of
predicted vs observed data and from plots of residuals.
The absorption rate constant (ka), lag-time (tlag), elimin-
ation rate constant (ke), elimination half-life (t~), apparent
volume of distribution (Vd/F, F=absorption fraction), and
apparent clearance (CLlF) were estimated by the ADAPT II
program for each patient. The maximum concentration
Cmax(l) and the time to reach the Cmax(l) Tmax(l) in the first
dosing interval was calculated by Cmax(l)=[(D·F/Vd)(ka/
ke)(ke/(ke-ka))] and Tmax(l)=[(l/(ka-ke))(ln(ka/ke))] respect-
ively [19], where D represents the dose.
The average concentration at steady state (Css ) was
calculated for each patient by using the van Rossums
equation/" Css=[(D/r)/(CLlF)], where 'T is the dosing
interval. The median of 'T for each patient was used for
this purpose.
In each case the time to reach 90% of the steady state
concentration (Tess (90%)) was calculated using the equation
[21] Tess (90%)=3.3·t~.
Simulation of the recommended dosing schedule was
done in Quattro Pro 6.0 using the equation,
where n represents the number of doses given.!"
Results
Twenty-three children were included in the study. Two were
excluded because of mishandling of saliva and serum
samples. Patient characteristics of the remaining 21 chil-
dren, individual doses and length of paracetamol treatment
(LOT), which was determined as the time from first to last
paracetamol dose according to the protocol was adminis-
tered, are shown in Table I.
No paracetamol was detected in the serum or saliva
samples taken before administration of the first study dose.
 T.W.Hahn et al.

Table 1 Patient and clinical data for all patients. BMI=body mass index 22 calculated as [(body weight in kilograms)/(height in merresr'], BSA (in m2)=body
surface area" calculated as [(body weight in kiiograms)0.425 (height in centimetres)o.725X71.84XIO-4j, LOT=length of treatment, determined as the time from
first to last administration of paracetamol suppositories. *Patients are not included in calculation of mean (SD), median, or range. **Only one dose was given
(see text for details)

Patient Age Sex Weight Height BMI BSA Dose No. of doses LOT No. of saliva and
(yr) (MIF) (kg) (em) (kg m- 2 ) (nr') (mg kg") (n) (h) blood samples (n)

I 7.0 F 20.0 120.0 13.9 0.83 25.0 5 21.8 12

2 7.0 M 28.0 129.0 16.8 1.00 26.8 5 19.5 5
3 8.0 M 23.0 115.0 17.4 0.85 23.9 9 43.8 23
4 3.0 M 16.0 98.0 16.7 0.65 23.4 13 65.8 15
5 9.0 F 24.0 26.0 16 94.8 14
6 4.0 M 17.0 110.0 14.0 0.72 22.1 12 69.98 19
7 6.0 M 24.0 122.0 16.1 0.91 22.9 17 92.8 24
8* 7.0 M 20.0 120.0 13.9 0.83 25.0 I 0** 5
9 9.0 M 37.0 150.0 16.4 1.26 27.0 8 40.4 13
10 10.0 M 25.0 128.0 15.3 0.95 25.0 6 46.6 10
11* 6.5 M 23.5 125.0 15.0 0.91 23.4 I 0** 3
12* 3.0 M 18.0 102.0 17.3 0.71 27.8 I 0** 4
13 0.2 M 6.0 63.0 15.1 0.31 20.8 13 63.4 13
14 11.0 F 38.0 155.0 15.8 1.32 26.3 12 71.8 24
15* 5.0 F 21.5 114.0 16.5 0.81 25.6 I 0** 3
16 0.2 F 5.6 59.0 16.1 0.29 22.3 17 95.6 19
17 5.0 M 19.0 109.0 16.0 0.76 26.3 16 93.3 21
18 0.2 M 5.5 61.0 14.8 0.30 22.7 12 67.6 13
19 0.2 M 5.2 59.0 14.9 0.28 24.0 16 91.3 19
20 7.0 M 32.0 139.0 16.6 1.12 23.4 9 44.3 13
21 3.0 M 15.1 100.0 15.1 0.65 24.8 9 48.9 13
Mean 5.3 20.0 107.8 15.7 0.76 24.3 11.5 63.0 15.9
SD 3.6 10.2 31.0 1.0 0.33 1.8 4.0 24.4 5.2
Median 6.0 20.0 112.5 15.9 0.80 24.0 12.0 65.8 14.0
Range 0.2-11.0 16/5 5.2-38.0 59.0-155.0 13.9-17.4 0.28-1.32 20.8-27.0 5-17 19.5-95.6 5-24

Saliva-serum correlation
30 A
Thirty-two paired samples (n=64) were available for
I"
correlation analysis. The samples were obtained from 12 .~ 25
different children aged between II weeks and 11 yr. The
.s 20
CJ)

data are depicted in Figure l A. Regression analysis resulted

0
in a Pearson's Correlation coefficient (r) of 0.91 (P<O.OOl). E
The constant of the regression line was not significantly E1CIl 15
0
different from zero (P=0.6) and the data were then fitted ~
Cll 10
0.
to the simpler model forcing through the origin. The Cll
.2: 5
relationship between serum and saliva concentrations could ro
(J)
be described by the following equation (mg litre."):
0
0 5 10 15 20 25 30
concentration.jj, va=O. 92 X concentration.s.j.;
B
The ratio between saliva and serum was calculated to be • •
0.92±0.26 (Fig. IB).
0
.~ I
• •
.1
E • •
Pharmacokinetic modelling 2 •• • • • JfI, ••
•
CIl
•
Data from 17 children were used in the following modelling ~ •• •• •
as four children (8, 11, 12 and 15 in Table 1) were excluded
.2:
ro
(J)
•
because of insufficient data.
Individual parameters of ka , tlag, k.; t~, Vd/F, CLlF, Css and o+----.----r-----r---r---,-,--.--.--...----.---,----,
TC ss (9 0 % ) are given in Table 2. - o 5 10 15 20 25 30
In Figure 2A a serum concentration-time profile for a Serum paracelamol (mg litre- 1)
typical patient is shown. One patient (14) among the 17
Fig 1 (A) Plot of saliva vs serum concentrations. The line indicates the
patients subjected to pharmacokinetic modelling was line of regression: concentration'.liva=0.92Xconcentration serum- (B) Ratio
excluded from average estimates in Table 2 because this between saliva and serum concentrations. The mean ratio was 0.92 (SD
patient exhibited very different parameter values and did not 0.26). The line indicates the line of unity.

514
 Pharmacokinetics of rectal paracetamol

Table 2 Pharmacokinetic data. k,=absorption rate constant; ljag=lag time; ke=elimination rate constant; I,=elimination half-life; VdlF=apparent volume of
distribution; Cma'(l)=maximum concentration in the first dosing interval; Tm"(l)=time to reach Cm'''(l); CLlF= apparent clearance, F=absorption fraction;
1=dosing interval; C,,=average concentration in steady state; Tc:« (90%)=time to reach 90% of C". *Patient is not included in the calculation of mean, SD,
median, or range (see text for details)

Patient k a (h- I ) flag (h) k; (h- I ) f ll 2 (h) VdlF Tmax(l) Cmax(l) CLIF 't (h) c, Tess (90%)
(litre kg") (h) (mg Iitrc'") (litre kg"! h-I) (mg lltre") (h)

1 0.95 0.29 0.12 6.00 2.65 2.49 6.99 0.31 5.00 16.32 19.79
2 3.96 0.87 0.06 11.46 2.74 1.07 9.17 0.17 4.38 36.91 37.81
3 0.28 0.00 0.28 2.45 0.75 3.53 11.75 0.21 5.35 21.01 8.09
4 0.19 0.25 0.19 3.64 1.04 5.26 8.28 0.20 6.00 19.84 12.02
5 9.29 0.98 0.19 3.57 1.26 0.43 19.05 0.24 6.00 17.77 11.78
6 0.52 0.00 0.12 5.98 2.02 3.67 7.03 0.23 6.00 15.66 19.72
7 0.55 0.76 0.55 1.26 0.50 1.81 16.87 0.28 6.00 13.84 4.14
8
9 0.54 0.68 0.54 1.27 0.83 1.84 11.99 0.45 6.00 9.99 4.20
10 0.30 0.41 0.29 2.35 1.07 3.39 8.74 0.31 8.50 9.37 7.76
11
12
13 0.36 0.77 0.36 1.92 0.86 2.77 8.92 0.31 5.00 13.39 6.34
14* 1.61 0.00 0.03 20.82 9.46 2.52 2.58 0.28 6.00 13.92 76.25
15
16 0.65 1.55 0.65 1.07 0.86 1.54 9.57 0.56 6.00 6.69 3.52
17 0.40 0.33 0.33 2.10 1.11 2.75 9.57 0.37 6.00 11.96 6.94
18 0.53 0.05 0.53 1.32 0.78 1.90 10.73 0.41 6.00 9.19 4.35
19 0.84 0.00 0.30 2.29 1.05 1.91 12.92 0.32 5.84 12.97 7.56
20 1.52 0.72 0.14 5.12 1.96 1.73 9.39 0.27 5.50 16.06 16.89
21 1.17 0.59 0.21 3.36 1.64 1.79 10.40 0.34 6.00 12.22 11.08
Mean 1.38 0.52 0.30 3.45 1.32 2.37 10.71 0.31 5.85 15.20 11.38
SD 2.22 0.42 0.17 2.59 0.66 1.10 3.09 0.10 0.84 6.78 8.55
Median 0.55 0.50 0.29 2.40 1.06 1.91 9.57 0.31 6.00 13.61 7.93
Range 0.19-9.29 0-1.60 0.06-0.65 1.07-11.46 0.50-2.74 0.43-5.26 6.99-19.05 0.17-0.56 4.38-8.50 6.69-39.91 3.52-37.81

reach steady state within the 75 h of sampling. The serum 35 A

concentration-time profile for this patient is shown in 'I
Figure 2B. ~ 30 - Model prediction
• Observed concentration
The Pearson's Correlation coefficients (r) between the OJ
-S 25
apparent volume of distribution CVd/F) and age, height, body
weight, and body surface area (BSA)23 were found to be
~ 20
ell
0.57, 0.70, 0.67 and 0.69 respectively. The Pearson's ~ 15
Correlation coefficients (r) for the relationship between
e
~ 10
the apparent clearance (CLIF) and the patient characteristics E
mentioned above were 0.74, 0.79, 0.83 and 0.82. All ~ 5
(j)
correlations were statistically significant (P<0.05) and are 0-+----,-,..----,-,..----,-,..----,-,..----,,--,
depicted in Figure 3A-D. There was no correlation between o 10 20 30 40 50 60 70 80 90 100
body mass index (BMI)22 and VctlF or CLiF. Patients 8, 11, 35 B
12,14 and 15 were excluded from calculations of Pearson's 'I
.~ 30
correlation coefficients.
Concomitant administration of drugs was registered for E 35
all patients (Table 3). There are no reports on interactions (5 20
E
between paracetamol and any of these drugs/" and regional ell
CD 15
• •
anaesthetic techniques are not known to affect paracetamol ~
pharmacokinetics. ~ 10
E
2 5
CD
(j)

Discussion 10 20 30 40 50 60 70 80 90 100
Time (h)
Saliva sampling represents a non-invasive method, which is
not associated with pain and the risk of infection present in Fig 2 Observed vs predicted serum concentration time-profiles of
blood sampling. It is especially advantageous when multiple paracetamol. (A) A typical patient (no. 19). (B) An atypical patient (no.
samples are required. The good correlation between saliva 14).

515
 T.W.Hahn et at.

100 A 20 100 B 20

75 0 • 15 f' 75 0 • 15 ,.
W s: W s:
0 0
~
C/)
.~
= 50
C/)

= 50
(])
0 0
~
~
10 ~ ~ 10
"!:: LL
"!::"0
po=='il
LL
>
"0
> :::J 0 :::J
25 5 o 25
• 5 o

0 0 0
0 2 4 6 8 10 0 10 20 30 40
Age (yr) Weight (kg)

100 C 20 100 0 20

75 0 • 15 ,. 75 0 • 15 ,.
W .!:: W s:
0 0
~
C/)

.~
C/)

=
po
.~ ~
=
po

"!::
50 10
LL
LL
50 10
=
LL
>
"0
:::J ~ 0 :::J
25 5 o 25 5 o

0 0 0
60 80 100 120 140 160 0.4 0.6 0.8 1.0 1.2 1.4
Height (em) BSA (m2 )

10 Vd/F(I) • CUF II - - Regression Vd - Regression CL

I
Fig 3 Volume of distribution (VjF) and clearance (CLIP) compared to age, weight, height and BSA. The lines indicate lines of regression. Correlation
coefficients (r) between VjF and weight, height, and BSA were 0.57, 0.70, 0.67 and 0.69, respectively, and between CUP and the parameters
mentioned above correlation coefficients were 0.74, 0.79, 0.83 and 0.82. All correlations were statistically significant (P<0.05).

After administration of paracetamol suppositories, the

Table 3 Concomitant drug administration during study period. Numbers
refer to patient numbers in Tables I and 2
Concomitant drug
Diclofenac
Morphine
Epidural bupivacaine
Fentanyl
Alfentanil
Pethidine
Benzylpenicillin
Cefuroxime
Dexamethasone
Ondansetrone
Furosemide
and serum concentrations of paracetamol found in the
children in our study is in agreement with findings in
another study of adult postoperative patients.l? where the
correlation coefficient (r) after rectal administration of
paracetamol was 0.99 compared with 0.91 in our study. AI-
Obaidy and colleagues'f found a correlation coefficient (r)
of 0.95 after oral dosing in six paediatric patients. This
suggests that saliva samples can replace blood samples in
assessment of paracetamol concentrations in children in the
postoperative period. Saliva sampling has been observed to
result in cost savings compared to blood sampling and to be
more acceptable to parents and children.i''
absorption rate was faster than or equal to the rate of
elimination in all children, but large variations were seen in
Patients exposed
the absorption phase and the resulting steady state concen-
1, 2, 3, 5, 7, 9, 11, 17 trations. The absorption rate constant (ka ) observed in our
5,9, II, 17, 19,20,21 study was 1.4 (2.2) h- I . After administration of suppositor-
4, 6, 10, 21
4,5,21 ies to children, Birmingham and colleagues.' reported a
6 typical k; of 0.3 h- 1 and Coulthard and colleagues'' found a
5 mean ka of 1.4 h- I .
I, 2, 3, 7, 9, II, 17
5 Various explanations have been offered for this unpre-
1, 2, 7, 9, 11, 17 dictable absorption pattern from paracetamol suppositories,
9, 17,21 but none have been proven. Premature defaecation would
14
reduce the amount of drug available for absorption, but no
premature defaecation was observed in our study. Rectal pH
and rectal contents may also influence the absorption pattern
of rectally administered drugs [27]. In children, the rectal
pH varies from 7.8-11.4 (95%-confidence intervalj.r'' For
paracetamol (pKa=9.5) this may influence bioavailability,
since only undissociated drug passes biological membranes
and the degree of dissociation for paracetamol will vary
from 2 to 99% in this pH range (% molar dissociation=[l 00/
(I +antilog pKa_pH)]).29
Children seem to absorb paracetamol from suppositories
faster and to a greater extent than adults. Using the same
type of suppositories in a single dose of 26-36 mg kg- 1 in
adults after minor gynaecological laparoscopic surgery, 16
the highest mean (so) observed concentration was 8.4 (3.5)
mg litre"! compared with the Cm a x after the first dose in our

516
 Pharmacokinetics of rectal paracetamol
study which was 10.7 (3.1) mg litre"! after administration of
21-27 mg kg-I. Giving 23.9 (4.2) mg kg- l to children
younger than 160 days, Hansen and colleagues 30 observed a
Cm ax of 10.9 mg litre-I. In a study of adults, 16 Tmax was not
reached within 4 h after administration. In contrast, Tmax in
the first dosing interval for the children in our study was 2.4
(1.1) h. Values of Trnax found by other investigators after
single dose administration of paracetamol suppositories to
children are between approximately 1 and 3 h. 3 48 1030-32 In
pre-term neonates, the absorption seems to be slower, van
Lingen and colleagues found Tmax values of 3.9-5.1 h in
children 28-36 weeks of gestational age. 33
The limited space in the rectum of infants and small
children compared with suppository size may favour a more
efficient contact with the rectal mucosa and, consequently,
improved absorption. Also, the rectal mucosa and colonic
blood flow may be altered in children, but this has not been
proven.
Differences in the concentration reached in individual
patients may also be explained by a variability of venous
drainage from the rectum. Paracetamol undergoes variable
hepatic first-pass metabolism" 34 If a drug is administered
in the upper part of rectum it will be subject to the hepatic
first pass effect whereas drugs in the lower part of the
rectum will bypass the liver via the inferior vena cava?5
Administration of multiple suppositories, as was the case for
some children in our study, could also contribute to the
variable absorption.'? The degree of rectal anastotomic
channels has been proposed to counteract the rectal venous
drainage pattern.'
The volume of distribution (VdIF) in our study is in
agreement with values found in other paediatric stud-
ies. 11 3237 The lower correlation coefficient (r=0.57)
between age and VdlF implies that calculation of a loading
dose should not be based on age but rather on weight, height
or BSA, which show higher correlations to the apparent
volume of distribution (r=0.67-0.70).
Only 4% of paracetamol is excreted unchanged in the
urine in both neonates, children and adults. The rest is
metabolized to paracetamol-sulphate and glucoronide in
varying amounts depending on age. 38 39 Even though
neonates, infants and children under 12 yr have a limited
ability to conjugate phenolic drugs they are able to
compensate for this by a well-developed capability for
sulphate conjugation, resulting in overall paracetamol
elimination half-lifes after single doses similar to adult
values. 3940 In our study ti,2 after repeated dosing, was
between 1.1 and 11.5 h with a mean (SD) of 3.5 (2.6) h, and
for one patient (14) the t~ was as long as 20.8 h, but the
predicted steady state concentration for this patient was in
the therapeutic range. The long t~ may reflect a very slow
rate of absorption, i.e. a flip-flop model, and not a reduced
clearance, as the steady state concentration for this patient
was comparable with the steady state concentration of the
other patients. Repeated doses to children aged between 6
517
months and 6 yr in a study by Nahata and colleagues
resulted in a t:2 of 2.2 h. 14
The relatively good correlation (r=0.72, P<0.05) between
CLiF and age suggests that the ability to eliminate
paracetamol does increase slightly with age (Fig. 3A).
However, body weight (Fig. 3B) and BSA (Fig. 3D) seem to
correlate better with elimination capacity (r=0.83 and 0.82,
P<0.05). In six pharmacokinetic studies of paracetamol
including a total of 270 children between 2 months and 17 yr
the terminal half-life after single doses ranged from 1.7 to
4.7 h.4 811303237 In pre-term neonates the half-life seems to
be prolonged. For example, van Lingen:' observed a t:2 of
4.8-11.0 h in this age group.
The average concentration reached at steady state (C,) in
our study (15.2 (6.8) mg Iitre") is well above the lower limit
for the accepted antipyretic concentration range, which has
been suggested to be 10-20 mg litre- l . 41-43 Only one patient
did not approach this concentration range at steady state.
Although no solid link has been proven to exist between
serum concentration of paracetamol and degree of analgesia
produced, the analgesic effect of paracetamol is believed to
be related, directly, to its serum conceotrauon" because of
its high lipid solubility and low protein binding in the
therapeutic concentration range. After tonsillectomy in
children two studies have reported relationships between
paracetamol concentration and degree of postoperative pain.
Anderson and colleagues' observed that 50% of children
experienced satisfactory analgesia at a concentration of 17
mg litre-1, and in another study, 13 acceptable pain scores
were associated with a paracetamol concentration above 10
mg litre-I.
The safety of repeated dosing of paracetamol in children
has been questioned, 14 33 45 and cases of toxicity after
repeated therapeutic doses'" 47 and supratherapeutic doses'"
have been reported. In our study the highest predicted
concentration at steady state was 36.9 mg litre- l which is
well below the limit of toxicitl 950 at 120 mg litre-I.
However, care should be taken when situations of malnu-
trition are present, because depletion of glutathione stores
could make children susceptible when sulphation and
glucoronidation pathways are saturated. 51-53
The maximum daily dose of paracetamol is controver-
sial,54 but the current oral paediatric dosing recommenda-
tion for paracetamol is a loading dose of 20 mg kg- 1 and a
maintenance dose of 15 mg kg- l every 4 h55 with an upper
limit of 90 mg kg- l per day" Rectally 15-20 mg kg- l is
given every 4 h commonly.V but this may produce
inadequate concentrations. 5859
To reduce the time to reach steady state concentrations,
which in our study were not reached until nearly 12 h after
administration of the first dose, a loading dose should be
given.
We used mean parameter values found in this study
(k a=1.4 h- l , tl ag =0.5 h, ke=0.3 h- l , VdIF=1.3 litre kg-I, CLI
F=0.3 litre kg- lh- l ) to simulate a paracetamol dosing
schedule with a loading dose of 35 mg kg- 1 and a
 T.W.Hahn et al.

,. 20 5 Anderson B, Kanagasundarum S, Woollard G. Analgesic efficacy

of paracetamol in children using tonsillectomy as a pain model.
.~ Anaesth Intens Care 1996; 24: 669-73
en 15 6 Lin Y-C, Sussman HH, Benitz WE. Plasma concentrations after
E- rectal administration of acetaminophen in preterm neonates.
<5
E Paediatr Anaesth 1997; 7: 457-9
<1l 10
Q) 7 Anderson BJ, Holford NHG, Woollard GA, Chan PLS.
o
e<1l Paracetamol plasma and cerebrospinal fluid pharmacokinetics
0. 5 in children. BrJ Clin Pharmacol 1998; 46: 237-43
E 8 Coulthard KP, Nielsen HW, Schroeder M et al. Relative
'"
Oi bioavailability and plasma paracetamol profiles of Panadol®
(J)
O-tL---,-----,,----,-------,-----,------, suppositories in children. J Paediatr Child Health 1998; 34: 425-31
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Plasma concentrations after high-dose (45 mg/kg) rectal
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acetaminophen in children. Can J Anaesth 1995; 42: 982-6
was done using the equation:
I I Anderson BJ, Woollard GA, Holford NHG. Pharmacokinetics of
C(t) = _
FD k
* __ * [(1 -
<I _
e-nk"T)
* _e-k.(t-t'"g)_ rectal paracetamol after major surgery in children. Paediatr
Vd ka-ke (l_e k• T ) Anaesth 1995; 5: 237-42
12 Kolloffel WJ, Driessen FGWHM, Goldhoorn PB. Plasma
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18: 105-8
where n represents the number of doses given.!"
13 Anderson BJ, Holford NHG, Woollard GA, Kanagasundarum S,
Mahadevan M. Perioperative pharmacodynamics of
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tories every 6 h (Fig. 4). 411-21
14 Nahata MC, Powell DA, Miller MA. Acetaminophen
In conclusion, after administration of paracetamol sup-
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