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Israel Journal of Veterinary Medicine  Vol. 69 (3)  September 2014 Kumar, S. 130
INTRODUCTION
Ceftriaxone is efective in a variety of infections including
meningitis, septicemia, pyoderma, colibacillosis, surgical pro-
phylaxis and infections of the urinary tract, respiratory tract,
wounds, soft tissues and joints (1). It is characterized by its
excellent activity against Gram-negative pathogens includ-
ing Salmonella, Shigella, Proteus, Klebsiella, Enterobacter,
Pasteurella, Escherichia coli and Neisseria meningitidis. Te
relatively low Minimum Inhibitory Concentration (MIC)
of ceftriaxone against Gram-negative bacteria makes it suit-
able for use in bacterial endometritis associated with Gram-
negative pathogens, most of which are resistant to the other
commonly used antibiotics (2). Te use of antibacterial drugs
that could penetrate into the udder parenchyma in therapeu-
tic levels is of considerable importance, particularly in severe
and life-threatening infectious conditions of the udder (3).
Tere is meager information on the penetration of ceftri-
axone from blood into milk. Although, some data are avail-
Intramuscular Pharmacokinetics and Milk Levels of Ceftriaxone in
Endometritic Cows
Kumar, S.,
1
* Srivastava, A. K.,
2
Dumka, V. K.
3
and Kumar, N.
4
Faculty of Veterinary Sciences and Animal Husbandry, Sher-E-Kashmir University of Agricultural Sciences and Technology
of Jammu, R.S.Pura, Jammu, India.
1
Division of Animal Reproduction, Gynaecology and Obstetrics, India.
2
National Dairy Research Institute, Karnal, India.
3
Department of Pharmacology and Toxicology, GADVASU, Ludhiana, India.
4
Dairy Microbiology Division, National Dairy Research Institute, Karnal, India.
* Correspondence: Dr. Sudershan Kumar, Associate Professor, Division of Animal Reproduction, Gynaecology and Obstetrics, Faculty of Veterinary Sciences
and Animal Husbandry, Sher-E-Kashmir University of Agricultural Sciences and Technology of Jammu, R.S.Pura Campus, Jammu ( JandK)-181102, India.
Cell: +91-9419190755, Tel: +91-191-2537348, Fax: +91-1923-250639, Email: vkdumka@yahoo.com; drsudarshandogra@yahoo.com
ABSTRACT
Disease conditions are known to alter the pharmacokinetics of antibacterials in bovines. Ceftriaxone is
efective for the treatment of bacterial endometritis particularly caused by Gram-negative pathogens.
In this regard, the plasma pharmacokinetics and milk levels of ceftriaxone were studied in healthy and
endometritic cows following single intramuscular administration. Peak plasma drug levels of 11.2 ± 0.329
and 4.68 ± 0.261 µg.ml
-1
attained at 30 minutes were found in healthy and endometritic cows, respectively.
Te drug was detected above the minimum inhibitory concentration (MIC) after up to 6 h of dosing
and the disposition followed a one-compartment open model. Te values of Vd
area
(apparent volume of
distribution), AUC (area under the plasma drug concentration-time curve), t
1/2β (elimination half life) and
P/C ratio (ratio of drug present in peripheral versus central compartment) were 0.67 ± 0.13 L.kg
-1
, 21.3 ±
0.86 µg.ml
-1
.h, 1.42 ± 0.13 h and 1.07 ± 0.25, respectively, in healthy cows and 1.35 ± 0.19 L.kg
-1
, 12.4 ±
0.56 µg.ml
-1
.h, 1.69 ± 0.47 h and 0.92 ± 0.39, respectively, in endometritic cows. Te use of antibacterial
drugs that could penetrate into the udder parenchyma in therapeutic levels is of considerable importance in
severe infectious conditions of the udder. Ceftriaxone was secreted into milk up to 36 h of administration.
An appropriate intramuscular dosage for ceftriaxone, would be 13 mg.kg
-1
repeated at 6 h intervals for the
treatment of endometritis in cows.
Keywords: Ceftriaxone, Endometritis, Intramuscular, Milk, Pharmacokinetics, Cows.
Israel Journal of Veterinary Medicine  Vol. 69 (3)  September 2014 131 Pharmacokinetics of Ceftriaxone in Endometritic Cows
able for ceftriaxone concentration in the milk of goats (4)
and ewes (3), there is no report of its levels in cow milk.
Furthermore, disease conditions have been reported to mark-
edly alter the pharmacokinetics of antibacterials in bovines (5,
6, 7, 8). Disposition kinetics of ceftriaxone after intramuscular
dosing has been conducted in bufalo calves (9, 10), ewes (3),
goats (4, 11, 12), camels (13) and dogs (14). However, there
is little information on the pharmacokinetics of ceftriaxone
in cattle species, except one study following intravenous ad-
ministration in endometritic cows conducted earlier in our
laboratory (15). In view of the paucity of pharmacokinetic
data of intramuscular ceftriaxone during endometritic condi-
tion in cattle, the present study was undertaken to determine
the pharmacokinetics and milk excretion of administration.
MATERIALS AND METHODS
Experimental animals and drug administration
Te experiment was performed in two groups of 8 healthy and
8 endometritis-afected crossbred cows between 3 to 9 years
age which had calved at least once. Endometritic cows were
selected on the basis of history of repeat breeding, thorough
per-rectal examination and physicochemical characteristic of
cervical mucus. Cows with history of repeat breeding, purulent
or muco-purulent estrual discharge or containing white fakes
and positive reaction to white side test (16) were considered
positive for endometritis. All the cows were examined per-
rectally to rule out any anatomical or reproductive disorders.
Animals were kept under loose housing system in clean and hy-
gienic experimental and milking paddocks with brick fooring,
asbestos roofng and sufcient space for the free movement of
the animals. All the animals were fed on a ration consisting of
concentrate mixture and green fodder with free access to fresh
water. Te experimental protocol followed the ethical guide-
lines on the proper care and use of animals and was approved
by the Institutional Animal Ethics Committee vide Director
Resident Instructions SKUAST ( J), Order No. AUJ/DRI/07-
08/D-08/2612-13 dated 18-1-2008. Ceftriaxone (Ceftriaxone
sodium; Intacef-3, Intas Pharmaceuticals, Ahmedabad, India)
was administered as 10 % solution at dose rate of 6.72 mg.kg
-1
body weight intramuscularly.
Collection, processing and storage of samples
Blood samples were collected just before and after drug ad-
ministration from the jugular vein into heparinized glass
tubes at diferent time intervals viz. 0, 1, 5, 10, 15, and 30
min and at 1, 2, 4, 6, 8, 12 and 24 h with the help of a plas-
tic catheter placed and secured before the administration of
drug. Plasma was separated by centrifugation at 8000 rpm
for 10 minutes and stored at -20°C for analysis to be con-
ducted on the following day of sample collection. Collection
of milk was carried out manually at 12, 24, 36 and 48 hours
after intramuscular administration of the drug. Te udder
was completely evacuated before the start of the experiment.
Te samples were kept in -20°C until analysis.
Analytical methods
Te concentration of ceftriaxone in samples was deter-
mined by microbiological assay technique using Escherichia
coli (ATCC 25922) as the test organism (17). Te test or-
ganism was cultured on antibiotic medium no. 1 at 37°C
for 24 h and a suspension was prepared in sterile normal
saline. Preliminary experiments were conducted to deter-
mine the actual amount of bacterial suspension to be used in
the preparation of seed layer. Te bacterial suspension of 0.5
naphlometer reading was diluted 30 times with sterile nor-
mal saline and 100 µl of the dilute suspension was transferred
to each petri-plate with the help of Cornwell Continuous
Pipetting Device (Becon Dickinson, USA). After solidif-
cation of the media, six wells of 9 mm diameter each were
punched at equal distance with the help of a punching device.
Tree alternative wells were flled with one plasma sample
and the remaining three wells with a reference solution of
ceftriaxone (0.1 µg.ml
-1
). Tese assay plates were incubated at
34°C for 6 h. At the end of incubation period, the diameter
of zone of inhibition of each well was measured with Fisher
Lilly Antibiotic Zone Reader (Fisher Scientifc Company,
USA). Nine replicates were analyzed for each sample. Te
assay could detect a minimum drug concentration of 0.01µg.
ml
-1
without diferentiating between the parent drug and its
metabolites.
Pharmacokinetic analysis
Te concentrations of ceftriaxone in plasma were plotted
on a semi-logarithmic scale as a function of time and the
pharmacokinetic parameters were calculated manually for
each animal using least square regression technique (18) by
applying the formulae: β = 2.303 × m where m, the regression
coefcient was calculated by least square regression tech-
nique and B was the zero-time plasma drug concentration
intercept of the regression line. A’ and Ka were calculated by
Reserch Articles
Israel Journal of Veterinary Medicine  Vol. 69 (3)  September 2014 Kumar, S. 132
the method of residual yields, t
½β = 0.693/Rate constant of
elimination, AUC = A/α + B/β, AUMC= A/α
2
+ B/β
2
, MRT
= AUMC/AUC, Vd
area
= Dose /β × AUC, Cl
B
= β × Vd
area
× 1000 (18). Te mean values and standard error (Mean ±
SE) of pharmacokinetic variables were obtained by averag-
ing the variables calculated for drug disposition after drug
administration to each animal.
Statistical analysis
Te mean values and standard errors (Mean ± SE) of drug
levels in plasma and milk as well as the pharmacokinetic
variables in endometritic cows were compared with the cor-
responding values obtained in healthy animals. Te difer-
ences between two means based on individual observations
were determined by Student’s t-test. Te signifcance was
assessed at P<0.05 and P<0.01 levels.
RESULTS
Figure 1 displays the mean plasma drug concentration-time
profle of ceftriaxone after intramuscular dose of 6.72 mg.kg
-1
body weight in healthy and endometritic cows. In healthy
cows, the plasma concentration of ceftriaxone was 2.13 ±
0.33 µg.ml
-1
at 1 min which attained peak level of 11.2 ±
0.33 µg.ml
-1
at 30 min and the drug levels above minimum
inhibitory concentration (MIC) were detected in plasma for
up to 6 h. In endometritic cows, the plasma drug concentra-
tion at 1 min was 1.81 ± 0.27 µg.ml
-1
, and the peak plasma
concentration (4.68 ± 0.26 µg.ml
-1
) was observed at 30 min.
Te drug levels above the minimum inhibitory concentra-
tion (MIC) were detected in plasma for up to 6 h. Based on
plasma level of ceftriaxone in healthy and endometritic cows,
various pharmacokinetic parameters were calculated and are
presented in Table 1.
Evaluation of results of plasma drug concentration of cef-
triaxone after intramuscular injection in healthy and endo-
metritic cows revealed that the disposition of ceftriaxone best
ftted one-compartment open model adequately described
by the exponential equation, C
p
= Be
-βτ
- A’e
-Kaτ
. In healthy
animals, the drug was rapidly absorbed into systemic circu-
lation from the intramuscular site of administration as was
evident from the high absorption rate constant (Ka) which
was 3.88 ± 0.79 h
-1
and the C
max
of 11.2 ± 0.33 µg.ml
-1
was
attained at 0.5 h. Te values of elimination rate constant (β)
Figure 1: Semilogarithmic plot of plasma concentration-time profle of
ceftriaxone in healthy and endometritic cows following its single intramuscular
administration of 6.72 mg.kg
-1
body weight. Values are presented as mean ± SE
of 8 animals. Te data was analyzed according to one-compartment open model.
Table 1: Disposition parameters of ceftriaxone in healthy and
endometritic cows (n = 8) following its single intramuscular
administration of 6.72 mg.kg
-1
body weight
Parameter Unit Mean ± SE
Healthy Endometritic
C
max
µg.ml
-1
11.2 ± 0.33 4.68 ± 0.26**
t
max
h 0.5 0.5
A’ µg.ml
-1
10.7 ± 2.52 4.56 ± 1.07
Ka h
-1
3.88 ± 0.79 3.16 ± 1.84
B µg.ml
-1
11.9 ± 0.49 6.74 ± 0.96**
β h
-1
0.49 ± 0.07 0.47 ± 0.26
t
1/2β
h 1.42 ± 0.13 1.69 ± 0.47
AUC µg.ml
-1
.h 21.3 ± 0.86 12.4 ± 0.56**
AUMC µg².ml
-1
.h 47.4 ± 1.90 32.20 ± 1.46**
Vd
area
L.kg
-1
0.67 ± 0.13 1.35 ± 0.19*
Cl
B
L.kg
-1
.h
-1
0.33 ± 0.11 0.56± 0.14
MRT h 2.27 ± 0.15 2.55 ± 0.31
td h 5.31 ± 0.26 4.66 ± 0.78
P/C ratio 1.17 ± 0.32 0.91 ± 0.38
*P<0.05, **P<0.01, C
max
and t
max
= peak plasma drug concentration and
time required to attain the peak concentration, respectively; A¢ and B =
zero-time plasma drug concentration intercepts of the regression lines of
absorption and elimination phases, respectively; Ka and β = absorption
and elimination rate constants, respectively; t
½β= elimination half-life;
AUC = area under the plasma concentration-time curve; AUMC = area
under the frst moment of plasma concentration-time curve, Vd
area
=
apparent volume of distribution; Cl
B
= total body clearance; MRT =
mean residence time; td = total duration of pharmacological efect, P/C
ratio = ratio of drug present in peripheral versus central compartment.
0.01
0.1
1
10
100
0 2 4 6 8 10 12 14
Time (h)
P
l
a
s
m
a
c
e
f
t
r
i
a
x
o
n
e
c
o
n
c
e
n
t
r
a
t
i
o
n
(
µ
g
/
m
l
)
P
l
a
s
m
a
c
e
f
t
r
i
a
x
o
n
e
c
o
n
c
e
n
t
r
a
t
i
o
n
(
µ
g
/
m
l
)
Time (h)
Reserch Articles
Israel Journal of Veterinary Medicine  Vol. 69 (3)  September 2014 133 Pharmacokinetics of Ceftriaxone in Endometritic Cows
and half-life of elimination (t
½β) were 0.49 ± 0.07 h
-1
and
1.42 ± 0.13 h, respectively, indicating rapid elimination of
the drug. Te apparent volume of distribution (Vd
area
) was
0.67 ± 0.13 L.kg
-1
, refecting moderate tissue distribution.
Area under curve (AUC) was 21.3 ± 0.86 µg.ml
-1
.h and area
under mean curve (AUMC) was 47.4 ± 1.90 µg².ml
-1
.h. Te
total body clearance (Cl
B
) which represents the sum of all
metabolic and excretory processes was 0.33 ± 0.11 L.kg.
-1
h
-1
.
Te mean residential time (MRT) was calculated to be 2.27
± 0.15 h and the ratio of amount of drug in peripheral to
that in central compartment (P/C) was 1.17 ± 0.32 showing
that greater fraction of the drug was available to produce
antibacterial activity at the site of infection.
In endometritic cows, some of the values of various
pharmacokinetic parameters were diferent from their cor-
responding values in healthy animals. Te absorption rate
constant (3.16 ± 1.84 h
-1
) was similar to the correspond-
ing value in healthy cows, however a lower C
max
of 4.68 ±
0.26 µg.ml
-1
was attained in the endometric cows at 0.5 h
compared to the healthy cows (p<0.01). Te values of β and
t
½β were 0.47 ± 0.26 h
-1
and 1.69 ± 0.47 h and similar to
the healthy cows. Vd
area
was 1.35 ± 0.19 L.kg
-1
. AUC was
12.36 ± 0.56 µg.ml
-1
.h and area under mean curve AUMC
was 32.20 ± 1.46 µg².ml
-1
.h both of which parameters were
signifcantly diferent from the healthy cows (p<0.001). Te
total body clearance was 0.56 ± 0.14 L.kg.
-1
h
-1
, mean resi-
dential time (MRT) was calculated to be 2.55 ± 0.31 h and
the P/C ratio was 0.91 ± 0.38, all three being similar to those
of the healthy coms.
Te milk levels of ceftriaxone at various time intervals
after its single intramuscular administration in healthy and
endometritic cows are given in Table 2. Initially at 12 h of
drug administration, the drugs levels were higher (313.6 ±
110.2 µg/ml) in healthy than during endometritis (148.1 ±
63.7 µg/ml). Subsequently the higher milk drugs levels were
maintained up to 36 h in healthy animals (1.99 ± 0.88 µg/
ml) compared to endometritic cows (0.93 ± 0.45 µg/ml).
Tereafter, the drug was not detected in the milk of both
healthy as well as of endometritic cows.
Using convenient dosage interval and the values of β and
Vd
(area)
of endometritic cows, the priming (D) and mainte-
nance (D
’
) doses of ceftriaxone to maintain the minimum
therapeutic concentration of were calculated from following
equations:
D = C
p
(min)
µ
.Vd (e
βτ
)
D
’
= C
p
(min)
µ
. Vd (e
βτ
-1)
Where, C
p
(min)
µ
is the desired minimum therapeutic
plasma level of ceftriaxone, β is elimination rate constant,
Vd is apparent volume of distribution and τ is the dosing
interval (19).
Based on the results presented, the priming and mainte-
nance doses of ceftriaxone were calculated from the pharma-
cokinetic data obtained in healthy animals as 9.02 and 8.71
mg.kg
-1
, respectively at an interval of 6 h for bacterial suscep-
tible to ceftriaxone with an MIC of 0.5 µg.ml
-1
However in
endometric cows, in order to maintain a minimum therapeu-
tic plasma concentration of 0.5 µg.ml
-1
, an appropriate intra-
muscular dosage regimen of ceftriaxone in endometritic cows
was 13.2 mg.kg
-1
followed by 12.6 mg.kg
-1
at 6 h intervals.
DISCUSSION
Disposition of ceftriaxone has also been reported to follow
a one-compartment open model in camels, goats and ewes
(3, 11, 12, 13). Te peak plasma level of the drug in healthy
cows was approximately 22 fold higher than the MIC of
ceftriaxone, however a lower peak plasma level was attained
at the same time in endometritic cows. Te plasma level
of ≥ 0.2 µg.ml
-1
for third generation cephalosporins is con-
sidered adequate against most species of sensitive bacteria
including Enterobacteriaceae spp. (20). However, a plasma
concentration of 0.25-2.0 µg.ml
-1
has been reported as the
minimum inhibitory concentration (MIC
90
) for cephalo-
sporins against common animal pathogens (21). MIC
90
of
ceftriaxone against various species of bacteria lies in the range
of 0.01-0.50 ug.ml
-1
(2). In this discussion, the higher value
of MIC (0.5 µg.ml
-1
) has been taken into consideration.
Te values of various pharmacokinetic variables of cef-
triaxone obtained following intramuscular injection in the
Table 2: Levels of ceftriaxone in milk of healthy and endometritic
cows (n=8) following a single intramuscular dose of 6.72 mg.kg
-1
body weight
Time after ceftriaxone
administration (h)
Drug levels in milk (µg/ml)
Healthy cows Endometritic cows
12 313.6 ± 110.2 148.1 ± 63.7
24 36.9 ± 15.1 3.43 ± 1.24**
36 1.99 ± 0.88 0.93 ± 0.45
48 ND ND
ND = Not detected, *P<0.05, **P<0.01
Reserch Articles
Israel Journal of Veterinary Medicine  Vol. 69 (3)  September 2014 Kumar, S. 134
present study were distinct from their corresponding values
reported in diferent species of domestic animals (Table 3).
Te signifcantly (P<0.05) large Vd
area
in endometritic
cows (1.35 ± 0.19 L.kg
-1
) in comparison to that in healthy
animals (0.67 ± 0.13 L.kg
-1
) indicated greater distribution of
the drug during endometritis. In agreement to the present
results, an increase in Vd
area
of ceftriaxone was also noted
following intravenous injection in endometritic cows (15).
Te observed increase in the apparent volume of distribution
could be attributed to the increased perfusion of the uterine
endometrium during the infammatory condition.
Te signifcantly (P<0.01) lower AUC of ceftriaxone in
endometritic cows (12.4 ± 0.56 µg.ml
-1
.h) in comparison to
its corresponding value in healthy cows (21.3 ± 0.86 µg.ml
-
1
.h), following intramuscular administration, in this study,
is in agreement with the decrease in AUC from 62.2 ± 23.3
to 37.0 ± 17.1 µg.ml
-1
.h observed during endometritis after
intravenous injection of the same dose of ceftriaxone in cows
(15). Te signifcant (P<0.01) decrease in C
max
(from 11.2 ±
0.33 µg.ml
-1
to 4.68 ± 0.26 µg.ml
-1
) and AUC of ceftriaxone
during endometritis may possibly be due to the infammatory
condition where more blood fow is diverted to the uterine
endometrium and hence reduced vascularity at the intramus-
cular site of administration of the drug.
Te elimination half-life (1.69 ± 0.47 h) and MRT (2.55
± 0.31 h) of ceftriaxone in endometritic cows was longer than
the t
½β (1.42 ± 0.13 h) and MRT (2.27 ± 0.15 h) in healthy
cows, although not statistically signifcant this possibly re-
fects a slower elimination of the drug during endometritis.
Consistent with the present observation, prolongation in
elimination half-life from 1.02 ± 0.07 h to 1.56 ± 0.25 h and
MRT from 1.55 ± 0.25 h to 2.14 ± 0.34 h was seen after
intravenous injection of ceftriaxone in endometric cows in
comparison to healthy animals (15).
Total body clearance of ceftriaxone, which represents the
sum of metabolic and excretory processes was 0.33 ± 0.11
L.kg
-1
.h
-1
in healthy cows and 0.56 ± 0.14 L.kg
-1
.h
-1
in en-
dometritic cows, and statistically similar for both groups. A
similar diference in Cl
B
after intravenous injection from 0.3
± 0.09 L.kg
-1
.h
-1
to 0.56± 0.14 L.kg
-1
.h
-1
was observed of the
same dose of ceftriaxone during endometritis in cows (15).
High levels of ceftriaxone were attained in the milk of
both healthy and endometric cows up to 36 h of admin-
istration. Lower concentration of the drug was recovered
in the milk of endometritic cows as compared to that of
healthy cows throughout the milking period with signifcant
(P<0.01) diferences at 24 h. No drug could be detected in
milk of both healthy and endometritic cows after 48 h of
dosing. A similar trend was noted in the concentration of
ceftriaxone after intravenous administration where higher
drug levels were recovered in milk of endometritic cows than
that of healthy cows throughout the milking period (15). In
contrast, lower concentration of ceftriaxone (0.19 µg.ml
-1
)
has been reported at 12 h following intramuscular dose of
10 mg.kg
-1
in ewes (3).
Te pharmacokinetic data was used to determine an ap-
propriate intramuscular dosage regimen of ceftriaxone for
cows sufering from endometritis. Taking 6 h as a dosage in-
terval (τ), with a minimum therapeutic plasma level (Cp
min
µ
)
of 0.5 µg.ml
-1
and using the values of β and Vd
area
of endo-
metritic cows from Table 2, a suitable intramuscular dosage
regimen for ceftriaxone, would be 13 mg.kg
-1
repeated at 6
h intervals for the treatment of endometritis in cows. Tis
dose was higher than the intravenous dose of 9 mg.kg
-1
at 6 h
Table 3: Pharmacokinetics of ceftriaxone in diferent species of animals in relation to these variables in healthy and endometritic cows.
Species
C
max
(µg.ml
-1
) t
max
(h)
Ka (h
-1
)
Vd
area
(L.kg
-1
)
AUC (µg.ml
-1
.h)
t
½β (h)
MRT (h) Reference
Healthy cows 11.2 0.5 3.88 0.67 21.3 1.42 2.27 Present fnding
Endometritic cows 4.68 0.5 3.16 1.35 12.4 1.69 2.55
Calves - - - 1.91 32.6 1.94 - 2,22
Bufalo calves 15.8 0.5 15.1 40.0 4.38, 4.96 2.63 9,10,23
Camels 21.5 1.03 2.39 - 91.9 2.96 13
Ewes 23.2 0.75 2.15 - 77.0 1.77 3.02 3
Goats - - 4.12 - 52.9, 77.5 0.98, 1.44, 2.03 2.76, 1.65 4, 11, 12
Dogs - - - - - 1.17 - 14
C
max
and t
max
= peak plasma drug concentration and time required to attain the peak concentration, respectively; Ka = absorption rate constant; t
½β=
elimination half-life; AUC = area under the plasma concentration-time curve; Vd
area
= apparent volume of distribution; MRT = mean residence time.
Reserch Articles
Israel Journal of Veterinary Medicine  Vol. 69 (3)  September 2014 135 Pharmacokinetics of Ceftriaxone in Endometritic Cows
intervals suggested for endometritis in cows (15). Lack of any
signifcant adverse efect, rapid absorption and high value of
Vd (area) revealed that in the treatment of mild to moderate
bacterial infections, IM administration of ceftriaxone may be
recommended for efcacy.
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