REVIEWS OF INFECTIOUS DISEASES VOL.

5, SUPPLEMENT MARCH-APRIL 1983

1983 by The University of Chicago. All rights reserved. 0162-0886/83/0502-0028$02.00

Pharmacokinetics of Cefoperazone in Patients with Normal

and Impaired Hepatic and Renal Function
Ronald A. Greenfield, Andreas U. Gerber, *
and William A. Craig

From the Department oj Medicine, University oj Wisconsin;

and the Department oj Medicine, William S. Middleton
Memorial Veterans Administration Hospital,
Madison, Wisconsin

A number of new cephalospirin antibiotics have

recently been developed; these form a third generation of such drugs. Cefoperazone is a semisynthetic piperazine derivative, structurally related to
both piperacillin and cefamandole. This paper will
present a review of the pharmacokinetics of this
drug in normal subjects and in patients with impaired hepatic and renal function. Comparative
studies of cefoperazone with other cephalosporins
will also be discussed.
Serum Concentrations
Cefoperazone is not appreciably absorbed after
peroral administration, and, therefore, must be
given by either im or iv injection. There are a
number of published and unpublished studies of
the pharmacokinetics of cefoperazone in normal
individuals following im and iv administration [I11; Pfizer Pharmaceuticals, unpublished data].
The range of mean peak serum concentrations
after im injection, iv injection, or iv infusion of
various doses of cefoperazone is shown in table 1.
More rapid administration of a dose resulted in
Please address requests for reprints to Dr. William A. Craig,
William S. Middleton Memorial VA Hospital, 2500 Overlook
Terrace, Madison, Wisconsin 53705.
* Present address: Medizinische Universitatsklinik Inselspital, 3010 Bern, Switzerland.

higher initial serum concentrations. In those

studies in which various doses were used, peak
serum concentrations and areas under the serum
level-time curves (AUCs) were linearly related to
the dose (figure O. Furthermore, the Aues for
different doses of cefoperazone were similar for
all three methods of drug administration.
The mean serum concentrations after im injection or iv infusion of 1 g of cefoperazone over 15
min are shown in figure 2. Peak serum levels were
158 f,lg of cefoperazone/ml with iv infusion and 65
f,lg/ml at 1 hr with im injection. After eight hours,
serum concentrations had fallen to 7.2 f,lg/ml and
3.9 f,lg/ml for im and iv administration, respectively. In this crossover study, the Aues for both
routes of administration were virtually identical,
indicating complete bioavailability of cefoperazone after im injection.
Mean serum concentrations after I5-min iv infusions of 2 g of cefoperazone, cefamandole, and
cefazolin into six normal individuals are shown in
figure 3. Peak serum levels for cefoperazone of
244 f,lg/ml were greater than the values of 217 f,lg/
ml for cefazolin and 163 f,lg/ml for cefamandole.
Serum concentrations of cefamandole declined
more rapidly than did those for the other two
drugs and were <1 f,lg/ml after six hr. In contrast,
serum levels of cefoperazone and cefazolin were
still 2.4 f,lg/ml and 3.3 f,lg/ml, respectively, at 12

S127

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The pharmacokinetics of cefoperazone in normal subjects and in patients with hepatic

and renal dysfunction are reviewed. Peak serum concentrations and areas under serum
level-time curves are linearly related to dose. The range of mean peak serum concentrations after a 2-g dose of cefoperazone is 202-375 JAg/ml with iv injection or infusion and
111 JAg/ml with im injection. The serum half-life is 1.6-2.6 hr. Urinary excretion is
rapid, but only 15070-37070 of the dose is recovered in urine. The drug is not metabolized
significantly. Levels of drug in bile are many times higher than serum levels, and biliary
excretion represents the major pathway of cefoperazone elimination. Serum kinetics of
cefoperazone are not significantly altered by renal impairment. However, hepatic
dysfunction is associated with a two- to fourfold increase in serum half-life. Even in
these patients, drug accumulation was not observed after repeated administration of 1 g
of cefoperazone at 12-hr intervals. Major dosage modification should only be required
with concomitant renal and hepatic dysfunction.

S128

Greenfield, Garber, and Craig

Table 1. Ranges of mean peak serum concentrations

of cefoperazone after im injection, iv infusion (over
15-30 min), and iv injection (over 3-5 min) in normal
adults, as determined both by bioassay and high-performance liquid chromatography.
Mean peak serum concentrations (Jig/ml) after
Dose (g)

Injection (im)

0.25
0.5
1.0
2.0
3.0
4.0

Infusion (iv)

22
23-33
65-74
111

Injection (iv)
76
115-200
202-375
311-518

90-158
197-264
331-347
506

hr. In another crossover study involving 10 normal subjects, Lode et al. [4] observed mean peak
serum concentrations of 233 J.(g/ml for cefoperazone and 132 J.(g/ml for cefotaxime after iv infusion of 2 g over 30 min. The decline in serum
levels for cefotaxime was similar to that shown for
cefamandole in figure 3 and resulted in a mean
value of only 0.3 J.(g of cefotaxime/ml at 8 hr. In
contrast, the mean serum concentration of cefoperazone at 8 hr was 4.4 jAg/ml.
Mean serum concentrations in 14 normal individuals on the first and last day of a seven-day
crossover regimen of 2 g of cefoperazone every 12
hr and 1 g of cefamandole every 6 hr are shown in
figure 4. Although peak serum levels of both
drugs were higher on the last day than on the first
day (215 J.(g/ml vs. 197 JAg/ml for cefoperazone
and 80 J.(g/ml vs. 70 jAg/ml for cefamandole),
neither drug showed evidence of clinically significant serum accumulation after multiple doses.
Maksymiuk et al. [8] also observed no significant
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Half-life and Serum Clearance

The mean serum half-life of cefoperazone in studies involving normal subjects has ranged from 1.6
hr to 2.6 hr [1-11; Pfizer Pharmaceuticals, unpublished data]. Half-life values in individual subjects
have varied from 1.2 hr to 3.0 hr. In studies
using various doses of cefoperazone, the halflife has demonstrated only a slight dose dependency, with mean values ranging from 1.6 hr after a I-g dose to 2.1 hr after a 4-g dose [3]. In a
crossover study, the half-life of cefoperazone after
im injection was slightly longer than with infusion
(Pfizer Pharmaceuticals, unpublished data). In
comparative studies with other cephalosporins,
the half-life of cefoperazone was significantly
longer than those of cefamandole and cefotaxime,
but slightly shorter than the half-lives of cefazolin
and moxalactam [3, 4, 9, 10].
The serum clearance of cefoperazone has ranged
from 71 mUmin to 96 mllmin [1, 3, 4, 7, 10].
These values are less than those observed for cefotaxime (238 mUmin) and cefamandole (218 mIl
min) but simlar to those observed for cefazolin (61
mIl min) and moxalactam (88 mllmin).

A/

3w 500

Figure 1. (A) Mean peak serum

concentrations for various cefoperazone doses given by iv injection, iv infusion, and im injection in normal
volunteers. (B) Area under the serum
level-time curves from these same
studies. Data are from [3, 6; Pfizer
Pharmaceuticals, New York].

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NOTE. Data are from [1-11] and unpublished data (Pfizer

Pharmaceuticals, New York).

accumulation of drug in serum of cancer patients

with normal renal and hepatic function after multiple doses of cefoperazone of either 2 g every 12
hr or 1 g every 6 hr for seven or eight days. Fourteen additional patients, after being given an initial I-g loading dose of cefoperazone over 30 min,
received a continuous iv infusion of 8 g of cefoperazone per day for five to eight days. Serum
concentrations were relatively constant (with
minor day-to-day fluctuations) and ranged from
77 to 100 jAg/ml.

S129

Pharmacokinetics oj Cejoperazone

200

300

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IM-284

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6
TIME (hours)

Figure 2. Mean serum concentrations of cefoperazone

after iv infusion of 1 g of cefoperazone for 15 min into
18 normal volunteers and im injection of 1 g of cefoperazone in six of these volunteers. Areas under the serumlevel time curves for the two routes of administration are
also shown. Data are from Pfizer Pharmaceuticals, New
York.

Protein Binding
The binding of cefoperazone to serum proteins, as
determined by ultrafiltration or equilibrium dialysis, has varied from 87OJo to 93.5OJo [3, 12-14].
Balant et al. [13] examined the effect of drug concentration on the extent of protein binding of cefoperazone and observed values of 93.5OJo, 89OJo, and
43OJo at drug levels of 25 JAg/ml, 250 JAg/ml, and
5,000 JAg/ml, respectively. In our own comparative
study, the protein binding of cefoperazone, cefazolin, and cefamandole was 90.4OJo, 86.00/0, and
79.2 0/0, respectively, and demonstrated little variation over the concentration range of 10 JAg/ml120 JAg/ml [3].
Shimizu [14] studied the competitive proteinbinding capacities of bilirubin and cefoperazone.
Although bilirubin easily displaced cefoperazone
from serum proteins, cefoperazone had no significant effect on the protein binding of bilirubin.
This finding suggests that cefoperazone will not
adversely affect distribution of bilirubin in neonates. Similarly, Cashore et al. [15] found that in
vitro cefoperazone only weakly displaced bilirubin
from its primary albumin binding site. As these investigators note, however, further studies in vivo

234

12

TIME (hours)

Figure 3. Comparative mean serum concentrations of

cefazolin, cefamandole, and cefoperazone after iv infusion of 2 g over 15 min in a crossover study in six normal
volunteers. Data are from [3].

are necessary to determine if high serum levels of

cefoperazone will present a hazard of displacement
of bilirubin in jaundiced newborns. This observation is important since there is significant transplacental transfer of cefoperazone [14].
300

200 \
-::: 100

Cefoperazone (day t)
o Cefoperazone (day 1)
Cefamandole (day I)

~ 806"
~ 60

6 Cefamandole (day 1)

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U

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a:::
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8
6

4
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12

TIME (hours)

Figure 4. Mean serum concentrations on day and

day 7 following 15 min iv infusion of 2 g of cefoperazone
every 12 hr and 1 g of cefamandole every 6 hr for 7 days
each in a crossover study in 14 normal volunteers. Data
are from Pfizer Pharmaceuticals, New York

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en

Sl30

,...,

Greenfield, Garber, and Craig

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Cefazolin
Cefamandole
Cefoperazone

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o
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4
8
TIME (hours)

12

Figure 5. Mean cumulative urinary recovery SD of

cefazolin, cefamandole, and cefoperazone following iv
infusion of 2 g over 15 min in a crossover study in six
normal volunteers. Data are from [3].

Elimination
In studies of normal volunteers, the mean urinary
recovery of cefoperazone has ranged from 15070 to
37% [1-11]. The lowest values were observed with
im administration. Urinary recovery also increased slightly with increasing dose. Urinary excretion of cefoperazone is much lower than that
observed for other cephalosporins. The cumulative urinary recoveries of cefoperazone, cefamandole, and cefazolin in our own comparative study
are illustrated in figure 5. Whereas the 12-hr recovery of cefoperazone was only 23 % of a 2-g
dose, values of 66% and 94% were obtained with
cefamandole and cefazolin, respectively. In
another comparative study, Lode et al. [10] obtained a total urinary recovery of 25070 for cefoperazone, but 53% and 91 % for cefotaxime and
moxalactam, respectively.
The low urinary recovery of cefoperazone is not
due to conversion of the drug to metabolites. At
least six in vitro degradation products of cefoperazone have been identified [14; Pfizer Pharmaceuticals, unpublished data]. Although high-performance liquid chromatography has revealed the
presence in urine and bile of at least two of these
hydrolysis products of cefoperazone, these metab-

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Cefamandole
Cefoperazone

-L

1-2

-L

2-4

-L

4-8

-L

8-12

COLLECTION PERIODS (hours)

Figure 6. Mean urinary concentrations for successive
intervals following the iv administration of 2 g of cefazolin, cefamandole, and cefoperazone over 15 min to six
normal volunteers. Data are from [3].

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~
.-J

olites made up <1% of the total drug recovered

[14, 16]. Thus, cefoperazone does not appear to be
significantly metabolized.
The renal clearance of cefoperazone has varied
from 14 mUmin to 25 mUmin [1, 3, 4, 7-10]. The
ratio of renal clearance of cefoperazone to the
renal clearance of creatinine is 0.13 [6]. This value
is only slightly greater than that fraction of unbound cefoperazone in serum and suggests that
glomerular filtration, rather than tubular secretion, represents the primary route for the renal
elimination of cefoperazone. This concept is supported by the observation that probenecid has only
a minimal effect on the serum levels and half-life
of cefoperazone [14].
In spite of the lower amount of urinary elimination of cefoperazone, urine concentrations far exceed the MIC for susceptible pathogens. The mean
urinary concentrations of cefoperazone, cefamandole, and cefazolin at different intervals after an
infusion of 2 g over a 15-min period are shown in
figure 6. Levels of cefazolin in urine were consistently two to four times greater than those of cefo-

S131

Pharmacokinetics oj Cejoperazone

Distribution
The apparent volume of distribution of cefoperalone in various studies has ranged from 10 to 17
liters [1, 3, 4, 7-11]. In comparative studies, the
apparent volume of distribution of cefoperazone
was similar to that of cefazolin but lower than the

values for cefamandole, cefotaxime, and moxalactam [3, 4, 9, 10].

Published data on the penetration of cefoperazone into various body tissues and inflammatory
fluids is limited. In patients with respiratory infections, peak sputum concentrations have ranged
from 0.08 JAg/ml to 6.1 /-lg/ml and reflect only
0.2070-1.4070 of the simultaneous serum concentration [11, 22]. Concentrations in tonsillar tissue,
maxillary sinus mucosa, and nasal mucosa have
been higher, ranging from 3.1 /-lg/ml to 9.0 /-lg/
ml [2, 23]. Concentrations of cefoperazone in pelvic tissue have ranged from 29070 to 36% of the simultaneously obtained serum levels [24]. Cefoperazone concentrations of 7-60 /-lg/ml (7%-40070
of the simultaneous level in serum) were obtained
in ascitic fluid of 11 patients receiving 2 g of drug
iv [2, 25].
Cefoperazone does not penetrate into the cerebrospinal fluid (CSF) of adults with normal noninflamed meninges [26]. In neonates without
meningitis, the levels of cefoperazone in CSF
varied from 1.8 /-lg/ml to 8.0 /-lg/ml at 0.5-12 hr
after iv infusion of 50 mg of cefoperazone/kg
[27]. Concentrations of cefoperazone in CSF in 40
infants and children and in two adults with meningitis varied from 0.4 /-lg/ml to 35 /-lg/ml [28-31]. In
the two adults, CSF levels were 9-14 JAg/ml, which
represented 11 %-48% of the simultaneous concentrations in serum. Clearly, more data are needed
before any valid conclusions can be made about
the penetration of cefoperazone into CSF in
adults.

Effect of Renal Impairment

Since the renal clearance of cefoperazone in normal subjects is only 1'\J25OJo of the total serum
clearance, one would expect only a slight increase
in its serum half-life in patients with renal impairment. The range and mean of half-life values
observed in patients with various degrees of renal
impairment are summarized in table 2. The study
by Bolton et al. [7] compared the pharmacokinetics of cefoperazone in normal subjects with those
in renal patients maintained by chronic hemodialysis. They observed no significant difference in
mean serum levels, half-life, and serum clearance
between the groups with normal and severely impaired renal function. Minimal increases in half-

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perazone. Urinary concentrations of cefamandole

also exceeded those of cefoperazone, but only for
the first 4 hr. Nevertheless, concentrations of
cefoperazone in urine of >32 JAg/ml were maintained for at least 12 hr.
The marked difference between renal and total
serum clearance of cefoperazone indicates considerable extrarenal elimination. Since the drug is not
significantly metabolized, biliary excretion would
be the most likely route of elimination. However,
total biliary excretion of a drug is difficult to
quantitate because the methods of obtaining bile
(T -tube drainage and duodenal tube aspiration)
rarely result in a complete collection. Furthermore, patients with external drainage of bile usually have some element of hepatic dysfunction that
may alter the extent of biliary excretion. For example, Kemmerich et al. [17] recovered only 19070
of a 2-g iv dose of cefoperazone from a quantitative collection of T-tube bile. However, the prolonged half-life and compensatory increase in
urine elimination of cefoperazone indicate significant hepatic dysfunction in these patients.
Peak biliary concentrations of cefoperazone in
patients with T -tubes and relatively normal
hepatic function have ranged from 481 JAg/ml to
6,598 JAg/ml [14, 17-21] as measured by both bioassay and high-performance liquid chromatography. In a crossover study with cefazolin, bile
levels of cefoperazone at 1, 2, and 6 hr were
1'\J30-fold higher than those of cefazolin [20]. Even
at 6 hr cefoperazone concentrations in bile ranged
from 854 to 954 /-lg/ml. In a similar study in six patients, Kemmerich et al. [17] observed a mean bile
concentration of 367 JAg/mt during the 10-24 hr
after administration of cefoperazone. Despite the
fact that the high biliary levels of cefoperazone
imply significant biliary excretion, the total
amount of drug eliminated by this pathway has
not yet been adequately determined in humans. In
rats, biliary recovery of cefoperazone accounts for
79070 of the administered dose [21].

Greenfield, Garber, and Craig

S132

Table 2. Serum half-life of cefoperazone in patients

with various degrees of renal impairment.
Half-life of
cefoperazone
Reference

7
13
32
33

No. of
patients

Dose

6
6
4
10

3
2

(g)

Range
(hr)

Mean
(hr)

Creatinine
clearance
(mllmin)

1.2-3.5
1.1-2.9
1.9-3.0*
2.5-15.1

2.0
2.1
2.3
6.6

9-44
5-49
2-12

<7

* Calculated by least squares method from serum concentrations at 2-6 hr.

200

Effect of Hepatic Dysfunction

In contrast to the situation involving renal impairment, the extensive nonrenal clearance of cefoperazone, presumably into bile, suggests that the
pharmacokinetics of this drug would be significantly altered by hepatic dysfunction. Cochet et
al. [35] infused 2 g of cefoperazone iv over a 2hr period into eight healthy volunteers and six
patients with impairment of hepatic function (due
to viral hepatitis in four patients and alcoholic fatty liver and cirrhosis in two). The half-life of cefoperazone was significantly prolonged in patients

Figure 7. (A) Mean serum concentrations after a I5-min iv infusion of

1 g of cefoperazone into each of six
normal individuals and 13 patients
with liver disease. Data shown for
normals are results of a I5-min iv infusion of 2 g that have been normalized to 1 g for comparative purposes.
Data are from [3] and W.A.C., unpublished observations. (B) Mean
serum concentrations on days 1 and 3
following a I5-min iv infusion of 1 g
of cefoperazone every 12 hr for five
doses to each of five patients with
liver disease. Data are from W.A.C.,
unpublished observations.

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TIME (hours)

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life (~3.5 hr) were observed in some patients. Similar results were observed by Balant et al. [13] and
Aoki et al. [32]. However, Bailey et al. [33] observed much longer half-life values (5.0-15.1 hr)
in six of the 10 patients studied. None of these patients had a known hepatobiliary disorder or were
taking drugs that might alter the pharmacokinetics
of cefoperazone. On the other hand, when 1 or 2 g
of cefoperazone was administered every 12 hr for
five to 14 days to eight patients with severe chronic
renal failure, no drug accumulation occurred in
any patient [33]. Thus, on the basis of these reports, the serum kinetics of cefoperazone in this
dose range are not significantly altered by renal
impairment, and dosage modification is unnecessary in the presence of renal insufficiency alone.
However, Hoffler et al. [34] recommend modest
dose reduction for higher dosages in patients with
severe renal function impairment.

Renal impairment will, of course, reduce the

amount of cefoperazone excreted into the urine.
Bolton et al. [7] recovered only 0.2% of the administered 3-g dose in their patients with end-stage
renal impairment. The patients studied by Bailey
et al. [33] also had severe renal impairment (creatinine clearance of ~ 12 mllmin) but were not
yet on dialysis. They observed mean maximal
urinary concentrations of 192 ~g/ml (range, 19.6920 ~g/ml) following the I-g iv dose of cefoperazone. In patients receiving multiple doses of drug
for five to 14 days, mean concentrations of cefoperazone in urine at 6 hr were 87 11 ~g/ml and
258 32 ~g/ml following 1- or 2-g doses every 12
hr, respectively. Thus, concentrations of cefoperazone above the MI C of susceptible urinary pathogens can be achieved in most patients with severe
renal impairment.

S133

Pharmacokinetics oj CeJoperazone

100
o~

->ffi
>
o

80

a:
>- 60
a:
<t

~
::J

40

>

~
~

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~

20

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U

12
TIME (hours)

24

Figure 8. Mean cumulative urinary recovery after a

I5-min iv infusion of I g of cefoperazone into three patients with biliary obstruction, two patients with cirrhosis and hyperbilirubinemia, and three patients with cirrhosis and normal serum bilirubin. Six normal individuals were each given a I5-min iv infusion of 2 g of cefoperazone. Data are from [3] and W.A.C., unpublished
observations.

sidered members of one of three groups: patients

with cirrhosis and normal levels of bilirubin, patients with cirrhosis and jaundice, and patients
with biliary tract obstruction due to malignancy.
In the three patients with relatively complete biliary tract obstruction, 90070 of the administered
dose had been recovered in the urine by 24 hr.
Urinary recovery of cefoperazone in the five cirrhotic patients was directly related to the extent of
hyperbilirubinemia. Similar results have been observed by Cochet et al. [35]. This rate of recovery
provides further evidence that biliary excretion
is normally the primary route of cefoperazone
elimination.
The pharmacokinetic parameters for cefoperazone in normal individuals and in three patients
with biliary tract obstruction are compared in
table 3. Although the nonrenal clearance of cefoperazone was markedly reduced in the patients
with biliary obstruction, the renal clearance was
greater than in normal subjects. In fact, the ratio
of the renal clearance of cefoperazone to that of

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with liver disease (3.4-5.9 hr) compared with that

observed in normal controls (mean, 1.6 hr). We
have recently studied the parmacokinetics of cefoperazone in 13 patients with severe biliary tract
obstruction and cirrhosis diagnosed by biopsy
(author's unpublished data). About half of the patients with cirrhosis had accompanying hyperbilirubinemia. Mean serum levels of cefoperazone after a I-g iv infusion into those patients are shown
in figure 7A. Data from our previous study of normal subjects [3] have been normalized to a I-g
dose and are included for comparison. The mean
peak concentration in serum at the end of the infusion was 92 34 lAg of cefoperazone/ml and had
fallen to 10 7 IAg/ml after 12 hr. The half-life of
cefoperazone in these patients ranged from 2.8 hr
to 7.0 hr, with a mean of 5.0 hr. A similar prolongation of cefoperazone's half-life was observed
by Boscia et al. [36] in five patients with cirrhosis
and in six patients with mild hepatosplenic
schistosomiasis. Thus, hepatic dysfunction is
associated with a two- to four-fold increase in
half-life of cefoperazone. There was, however, no
correlation between half-life and the type or the
severity of liver disease as determined by blood
analysis in any of these studies.
Since the half-life of cefoperazone in patients
with hepatic dysfunction is still less than the dosage interval commonly used for this drug (12 hr),
one would expect only minimal serum accumulation of cefoperazone with multiple doses. Since
steady-state levels following multiple dosing occur
after four half-lives, this concept was tested by
comparing serum levels of cefoperazone on day 1
and day 3 in five patients receiving five I-g doses
of drug every 12 hr (figure 7B). Although mean
serum levels at the various sampling times on day
3 were 8070-22070 higher than values on day 1, no
patient showed significant serum accumulation of
cefoperazone. The half-lives of cefoperazone in
these patients on day 3 (range, 2.9-6.8 hr; mean,
4.5 hr) were similar to those observed after the initial dose (range, 2.8-6.6 hr; mean, 4.5 hr). Thus,
dosage modification below 1 g every 12 hr is not
required in patients with hepatic dysfunction, providing that renal function is relatively normal.
The cumulative urinary recovery of cefoperazone in the eight patients studied after a single
dose is illustrated in figure 8 and is compared with
results in normal subjects. The patients were con-

S134

Greenfield, Garber, and Craig

Table 3. Pharmacokinetic parameters of cefoperazone in six normal individuals and in three patients with severe
biliary tract obstructions.

Study group

Half-life
(hr)

Serum
clearance
(mllmin)

Nonrenal
clearance
(mllmin)

Renal
clearance
(mllmin)

Ratio of
cefoperazone:
creatinine
clearance*

1.9

75

5.6

24

61
3

14
21

0.13
0.28

Normals
Patients

Protein
binding (070)

90
65

* Ratio of renal clearance of cefoperazone to renal clearance of creatinine.

Hepatic dysfunction, especially biliary tract obstruction, would be expected to decrease the penetration of cefoperazone into bile. In a crossover
study, Rosenfeld et al. l compared the biliary concentrations of cefoperazone and cefamandole
after a single I-g dose in five postcholecystectomy
patients with T -tube drainage (figure 9). Peak bile
concentrations of cefoperazone ranged from 2.8
f.lg/ml to 1,100 f.lg/ml and correlated inversely
with the serum bilirubin level. Biliary concentrations of cefoperazone were generally higher and
persisted much longer than did those of cefamandole. Marti et al. [20] observed bile concentrations of 5-40 f.lg/ml in a patient with cholestatic
jaundice. In our own study in two patients with severe biliary tract obstruction and recent Ring catheter placement, biliary concentrations of cefoperazone ranged from 5 f.lg/ml to 38 f.lg/ml for 12 hr
after a single I-g iv dose. Thus, even with severe
1 Rosenfeld, M. B., Ratzan, K. R. A comparison of the
biliary tract excretion of cefoperazone and cefamandole. Unpublished data on file, Pfizer Pharmaceuticals, New York,

1981.

Bilirubin 0.5

1200
1000

Bilirubin 1.8

Bilirubin 1.7

500

800
600

ci.

400

200

20

a::

f-

100

u
w

80

iii

60

40
20

Bilirubin 4.0

Bilirubin 6.2

a ,
a

3
2

..L

..L

24

..L

3 6
2
TIME (hours)

..L

24

23"6

Figure 9. Bile concentrations of

cefoperazone and cefamandole after
iv infusion of 1 g of each drug to five
post cholecystectomy patients with
various serum bilirubin levels. These
unpublished data are reproduced
with permission from M. B. Rosenfeld and K. R. Ratzan, "A comparison of the biliary tract excretion
of cefoperazone and cefamandole,"
Pfizer Pharmaceuticals, New York,
1981.

Downloaded from http://cid.oxfordjournals.org/ at Russian Archive on December 5, 2013

creatinine had doubled in these patients. This

was most likely due to a marked reduction in the
protein binding of cefoperazone as a result of
the hyperbilirubinemia. This more rapid renal
elimination in the presence of hyperbilirubinemia
probably explains why cefoperazone's half-life did
not correlate with the severity of liver dysfunction.
Balant et al. [13] reported a half-life of 14 hr in
a patient with biliary obstruction and moderate
renal impairment. This value is much longer than
those observed in studies already cited. The enhanced renal excretion of cefoperazone in the
presence of biliary tract obstruction would make
renal function an important determinant of serum
half-life. We recently observed a half-life for cefoperazone of 11.1 hr in a patient with moderate biliary obstruction and a creatinine clearance of 32
mllmin (W. A. C., unpublished data). Following
five doses of 1 g of cefoperazone at 12-hr intervals, serum levels and AVCs were 1.5 times
higher. More information is needed on the pharmacokinetics of cefoperazone in patients with
concomitant hepatic and renal dysfunction.

S135

Pharmacokinetics oj Cejoperazone

biliary tract obstruction, potentially therapeutic

concentrations of cefoperazone can be obtained in
bile.

6.
7.

Summary
8.

9.

10.

11.

12.

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