ISRAEL JOURNAL OF
VETERINARY MEDICINE
Vol. 62 - No. 3-4 2007
CEFOPERAZONE PHARMACOKINETICS FOLLOWING SINGLE
INTRAVENOUS ADMINISTRATION IN CROSS BRED CALVES
Gupta J. K., Chaudhary R. K., and Dumka V. K .
Department of Pharmacology and Toxicology ,
College of Veterinary Science ,
Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana-141004, India
Phone: (O) 91 161 2414032
2400945
(Mo) 91 98720 91126
Fax: +91 161 2400822, +91 161
E. mail: vkdumka@yahoo.com
ABSTRACT
The pharmacokinetics and urinary excretion of cefoperazone after a single intravenous
administration of 20 mg.kg 1-into the jugular vein were investigated in crossbred calves (n =
4 .)The concentration of cefoperazone in plasma and urine samples was estimated by a
standard microbiological assay technique using Escherichia coli as the test organism. At 1
min after injection, the concentration of cefoperazone was 117 1..1 ± g.ml 1-in plasma,
which rapidly declined to 13.2 8.0 ± g.ml 1-at 30 min. The drug level above MIC 08was
detected up to 4 h in plasma. Cefoperazone was rapidly distributed from blood to the tissue
compartment as evidenced by the short distribution half-life (0.09 8.81 ± h), and the high
value of the rate of transfer of the drug from central to peripheral compartments ± 4.3(
8.4.h .)1-The AUC, elimination half-life and steady state volume of distribution were 29.0
1.84 ±g.ml.1-h, 2.05 8.1 ± h and 1.11 8.80 ± L. kg ,1-respectively. On the basis of the
pharmacokinetic parameters, an appropriate intravenous dosage regimen for cefoperazone
in calves would be 16 mg.kg 1-at 6 h intervals.
INTRODUCTION
Cefoperazone, a third generation cephalosporin, possesses broad spectrum activity
against gram-positive, gram-negative and anaerobic bacteria including H. influenza
Neisseria meningitides and Streptococcus pneumoniae. Clinical studies have
demonstrated cefoperazone to be a valuable drug in the treatment of calf diseases such
as diarrhoea and pneumonia associated with gram-negative bacteria resistant to many
commonly used antibiotics (1). Cefoperazone is suitable for the treatment of bone and
joint infections of horses (2), intensive care infections of humans (3) and has good
penetration into the pancreas indicating its usefulness in the prophylaxis and therapy
of secondary pancreatic infections (4). The pharmacokinetics of cefoperazone have
been determined in unweaned calves (5), buffalo calves (6, 7), horse (8), sheep (9)
and humans (10). However, such information is lacking in calves. Awareness of the
marked species variation in antimicrobial drugs kinetics, the present study was
undertaken to determine the pharmacokinetics, urinary excretion and an appropriate
dosage regimen after a single intravenous administration of cefoperazone in cross
bred calves.
MATERIALS AND METHODS
Experimental animals and drug administration
The study was conducted on 4 healthy male crossbred calves (Holstein Friesian x
Sahiwal), about one year old and weighing between 88-120 kg. The animals were
kept in the departmental animal shed under standard conditions of management for 2
weeks prior to the commencement of the study and were provided green fodder and
water ad libitum. All the animals were healthy at the time of experimentation. The
experimental protocol followed the ethical guidelines on the proper care and use of
animals. Cefoperazone (Panacea Biotech Ltd., India) was administered into the left
jugular vein at a dose rate of 20 mg.kg body weight as a freshly prepared 20 %
solution. The dose of the drug employed in the present study was comparable to the
doses used in other species of animals by previous workers.
Blood and urine sampling
The animals were kept in metabolic stalls of standard size. Blood samples (5 ml) were
withdrawn from the contralateral jugular vein into heparinized glass centrifuge tubes
before and at 1, 2.5, 5, 7.5, 10, 15, 30, 45 min and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and
12 h after administration of drug. Plasma was separated by centrifugation at 1300 g
for 15 min at room temperature and kept at -200C until analysis, which was done
usually on the following day. Urine samples were also collected from the animals at
predetermined time intervals of 2, 4, 6, 8, 10, 12, 18 and 24 h after administration of
drug. The metabolic stalls were designed so that urine excreted naturally by the
animals within a period was automatically collected without contamination or spillage
in the containers placed beneath the stalls. At the end of the given time interval, the
volume of total urine voided and collected in the container was measured for each
animal, and 5 ml samples were taken for analysis after filtration.
Analytical procedure
The concentration of cefoperazone in plasma and urine samples was estimated by a
standard microbiological assay technique (11) using Escherichia coli (ATCC 10536)
as the test organism. The assay plates were incubated at 370C for 12 h. At the end of
incubation, the diameter of zone of inhibition of each well was measured with a
Fisher Lilly Antibiotic Zone Reader (Fisher Scientific Company USA). For each
sample, 9 replicates were analysed and compared with the zone of inhibition of a
standard reference solution of cefoperazone (0.3 µg.ml-1). The concentration of
cefoperazone in the samples was calculated as µg.ml-1 of plasma or urine. The assay
could detect a minimum of 0.25 µg.ml-1 of cefoperazone without differentiating
between the parent drug and its metabolites.
Calculation of pharmacokinetic parameters
Pharmacokinetic parameters were calculated manually by the computed least-squares
linear regression technique by applying compartmental analysis (12). The mean
pharmacokinetic variables were obtained by averaging the variables calculated for
drug disposition after intravenous drug administration to each animal.
RESULTS
The mean plasma levels of cefoperazone in crossbred calves, at various time intervals,
after its single intravenous administration (20 mg.kg-1) are presented on a
semilogarithmic scale in Figure 1. At 1 min, the mean plasma drug concentration was
117 ± 17.2 µg.ml-1 which rapidly declined to 13.2 ± 0.8 µg.ml-1 at 30 min.
Evaluation of the results revealed that the disposition pattern of cefoperazone was
adequately described by the bi-exponential equation: Cp = Ae-αt + Be-βt, where, Cp
is the plasma level of cefoperazone at time t and e represents the base of natural
logarithm. A and B are the extrapolated zero-time intercepts of the distribution and
elimination phases, respectively. α and β are the rate constants of distribution and
elimination phases, respectively. The pharmacokinetic parameters that describe the
distribution and elimination pattern of cefoperazone in calves were calculated
manually and presented in Table 1. Using a convenient dosage interval and the values
of β and Vdarea from Table 1, the priming (D) and maintenance (D') doses of
cefoperazone were calculated from following equations:
D = Cpmin∝.Vd (eβτ), D' = Cpmin∝.Vd (eβτ-1),
where Cpmin∝ is the MIC of cefoperazone, β is the elimination rate constant and τ is
the dosing interval (13).
Table 1. Pharmacokinetic parameters of cefoperazone in crossbred calves (n=4)
following a single intravenous dose of 4 mg. kg-1 body weight
Cp0 = plasma drug concentration at time zero after intravenous dose; A and B = the
zero time intercepts of distribution and elimination phases, respectively; t1/2α =
distribution half life; K12 and K21 are rate constants of drug transfer from central to
peripheral and from peripheral to central compartment, respectively; P/C = ratio of
drug in peripheral to central compartment; AUC = area under the plasmaconcentration time curve; AUMC = area under the first moment of plasmaconcentration time curve; Vd(ss) = steady-state volume of distribution; ClB = total
body clearance of drug; MRT = mean residence time; t1/2β = elimination half life
Fig.1 Semilogarithmic plot of plasma concentration-time profile of cefoperazone
following a single intravenous injection of 20 mg.kg-1 body weight in crossbred
calves. Values are presented as mean ± SE of 4 animals. The data was analysed
according to two-compartment open model. Distribution (α) and elimination (β)
phases are represented by least square regression lines. The calculated points (o) of
distribution phase were obtained by feathering technique.
DISCUSSION
The pharmacokinetics of cefoperazone following intravenous administration in
crossbred calves was best described by the two compartment open model. In
accordance to our findings, the disposition curve of cefoperazone in unweaned calves
(5) was reported to follow a two compartment open model. However, in buffalo
calves after intravenous administration it followed a three compartment open model
(6), and in man (14). In the present investigation, the drug was detected in plasma up
to 8 h after dosing (0.57 ± 0.01 µg.ml-1). In contrast to the findings of this study, low
peak plasma levels of cefoperazone (57.3 µg.ml-1) were reported in unweaned calves
(5) and the drug was detected up to 10 h, whereas peak plasma levels of 86.9 µg.ml-1
were reported following intravenous administration of cefoperazone in buffalo calves
and the drug was present up to 24 h (6). The plasma level of ≥ 0.2 µg.ml-1 for third
generation cephalosporins is considered adequate against most species of sensitive
bacteria including enterobacteriaceae spp. (15). However, a plasma concentration of
0.25-2.0 µg.ml-1 has been reported as the minimum therapeutic concentration
(MIC90) of cephalosporins against common animal pathogens (16). In this discussion,
an average value of MIC (1.0 µg.ml-1) has been taken into consideration. Following
intravenous administration of cefoperazone, the highest concentration attained was
approximately 117 fold higher than the MIC of cefoperazone and the drug persisted
above the minimum therapeutic plasma level up to 4 h after administration.
The low value of distribution half-life indicated that cefoperazone was rapidly
transferred from the central to peripheral compartment in calves. Low values of
distribution half-life (0.368 h) were also reported for cefoperazone in unweaned
calves (5), however distribution of cefoperazone was slower in buffalo calves
(t½α2=1.14 h) following its intravenous administration (6). The rapid distribution of
the drug from central to peripheral compartment was further confirmed by higher
value of K12 than K21 and the high P/C ratio in the present study. However, low
values of K12 have been reported in unweaned calves (6.93 x 10-3 min-1) and buffalo
calves (0.299 h-1) after intravenous injection of cefoperazone (5, 6). The large steadystate volume of distribution established in the present study (1.11 ± 0.09 L.kg-1)
indicated extensive distribution of cefoperazone into various body fluids and tissues.
The volume of distribution of cefoperazone in the present study was less than its
corresponding value in unweaned calves, buffalo calves and man, however it was
more than that in horses. The volume of distribution of cefoperazone has been
reported to be 1.69 L.kg-1 in unweaned calves (5), 1.3 L.kg-1 in buffalo calves (6),
0.68 L.kg-1 in horses (8) and 9.44 L.kg-1 in humans (17).
The total body clearance of cefoperazone in the present study was 690 ± 20 ml.kg1.h-1 indicating the rapid clearance of the drug in calves. In contrast, a low value of
ClB (185.6 ml.kg-1.h-1) was reported following intravenous administration of
cefoperazone in buffalo calves (6). The elimination half-life of cefoperazone in calves
calculated in this study (2.05 ± 0.2 h) was in accordance to the t1/2β of 127.9 min in
unweaned calves (5). This was shorter than the half-life of 4.77 h in buffalo calves (6)
but longer than the t½ β of 0.48 h in rabbits (18), 0.7 h in sheep (9), 0.77 h in horses
(8) and 1.77 h in man (17).
Following intravenous administration of cefoperazone (20 mg.kg-1) in cross bred
calves, the drug could not be detected in urine up to 24 h of administration indicating
its non-renal route of excretion, and the major route of elimination of cefoperazone
has been reported via bile (17). The urinary recovery of cefoperazone under normal
conditions is in the range of 14-33 % in humans (19), 3.89 % in buffalo calves (6),
and 6% in rats (20). These findings suggest that cefoperazone may not be an
appropriate drug for the treatment of urinary tract infections in cattle.
The main aim of the pharmacokinetic study was to determine a satisfactory
intravenous dosage regimen of cefoperazone. On the basis of the present study, the
priming and maintenance doses of cefoperazone at a dosage interval of 6 h, were
calculated to be 16.7 and 14.6 mg.kg-1, respectively, or under field condition, for
most bacteria sensitive to cefoperazone, the most appropriate dosage regimen for
cefoperazone would be 16 mg.kg-1 to be repeated at 6 h intervals in calves.
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