Received: 24 March 2020
Accepted for publication: 24 November 2020
Slov Vet Res 2021: 58 (3): 95 –101
DOI 10.26873/SVR-1074-2020
UDC 615.21/.26:577.182.24:599.733.11
Original Research Article
Introduction
Ceftiofur is a semisynthetic 3rd generation 
cephalosporin with broad-spectrum antibacterial 
efficiency by inhibition of essential enzymes in cell 
wall biosynthesis resulting in a strong bactericidal 
effect (1, 2). It has been approved for veterinary 
medical uses in various animal species including 
equines, bovines, swine, sheep, and goats (3). The 
crystalline-free acid form of ceftiofur at a dose 
PHARMACOKINETICS OF THE LONG-ACTING CEFTIOFUR CRYSTAL-
LINE-FREE ACID IN ARABIAN SHE-CAMELS (Camelus Dromedarius)
Mahmoud Kandeel1,2, Wael El-Deeb3*,4, Mahmoud Fayez5, Ibrahim Ghoneim3
1Department of Biomedical Sciences, 3Department of Clinical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa, 
31982, Saudi Arabia, 2Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshikh University, Kafrelshikh, 35255, 4Department 
of Internal Medicine, Infectious Diseases and Fish Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt, 
5Veterinary Serum and Vaccine Research Institute, Cairo, Egypt
*Corresponding author, E-mail: weldeeb@kfu.edu.sa 
Abstract: Ceftiofur is an important broad-spectrum 3rd generation cephalosporin antibiotic. Owing to its time-dependent antimi-
crobial actions, the length of time of being above bacterial MIC is the critical point in using ceftiofur for chemotherapy rather than 
its peak of concentration. Consequently, this experiment was carried out to evaluate, for the first time, the pharmacokinetics of the 
long-acting ceftiofur crystalline acid-free form (ceftiofur-CAF) in camels. Ceftiofur-CAF 200 mg/ml suspension sterile solution was 
injected i/m at a dose 6.6 mg/kg. Blood samples were collected from the jugular vein in vacutainer tubes at 0, 0.13, 0.25, 0.5, 1, 2, 
4, 8, 12, 24, 48, 72, 96, 120, and 144 hours after administration of the drug. Ultrahigh Performance Liquid Chromatography-Mass 
Spectrometry (UPLC MS/MS) was used to measure serum concentration. Pharmacokinetic modeling was by a two-compart-
ment model. Pharmacokinetics of ceftiofur-CAF after single i/m injection in she-camels was best modeled in the two-compart-
ment model, where the drug slowly distributed to a second compartment with poor tissue penetration and high preference to the 
central compartment. In this study, the maximum plasma concentration (Cmax) was 9.29±0.42 μg/ml at Tmax equals 9.41±1.35 h. The 
area under the curve (AUC0-∞) was 354.1±57.22 μg/ml*h. The distribution and elimination half-lives were 7.42 and 46.13 h, respec-
tively. The mean residence time (MRT) was 42.01 h. Compared with the rapidly absorbed form of ceftiofur (ceftiofur-RAF) in cam-
els, there was almost similar maximal serum concentration but with delayed time to maximal concentration (Tmax), longer means 
residence time (MRT) and higher distribution and elimination half-lives. In terms of antibacterial efficacy, ceftiofur-CAF stayed 
above a previously recommended level of 0.2 μg/ml for 7 days, which can be achieved after a single i/m injection of 6.6 mg/kg. 
The obtained pharmacokinetics data in camels recommends repeated administration of 2 days apart for bacteria requiring MIC 
levels above 2 μg/ml.
Key words: Ceftiofur; pharmacokinetics; camel; cephalosporins
rate of 6.6 mg/kg can be used in two consecutive 
injections to cover a treatment course of 10 days 
(1). This is more beneficial than the laborious single 
daily dosing strategy.
Recently, camels have been reported to acquire 
serious respiratory infections caused by various 
bacterial and viral causative agents as middle east 
respiratory syndrome coronavirus (MERS CoV) or 
bacterial pneumonia (4, 5). Owing to the emerging 
nature of camel pathogens and their public health 
impact, proper therapeutic protocols have to be 
achieved.
Ceftiofur is an excellent choice in treating 
respiratory infections in horses, cattle, and swine (1). 
96 M. Kandeel, W. El-Deeb, M. Fayez, I. Ghoneim
The usage of a long-acting formula of ceftiofur 
is thought to deliver significant-high serum 
concentration of ceftiofur for at least 4 days 
after a single i/m injection in horses and other 
animals (1, 3, 6-9). This will be beneficial in 
creating antimicrobial coverage in treating 
camel pathogens and during mass treatment 
of respiratory infections in camels. Moreover, a 
single long-acting dose minimizes handling and 
avoid stresses on camels during restraining and 
repeated daily injections. Despite the availability 
of such long-acting ceftiofur preparation, 
its pharmacokinetics and drug disposition 
parameters in camels is not well understood. 
This study investigates for the first time the 
pharmacokinetics of ceftiofur crystalline acid-
free form (Ceftiofur-CAF) in Arabian she-camels. 
The obtained pharmacokinetic parameters were 
compared with that of the previously published 
results of ceftiofur immediate-release form 
(ceftiofur-IRF) in camels. This study will aid in 
designing dose frequencies and the proper design 
of antibacterial programs.
Materials and methods
Animals, facilities, and instruments
Three Arabian non-lactating 8 years old she-
camels were used in this study. The she-camels 
were housed in the facilities of the camel research 
center, King Faisal University. Camels did not 
receive any previous treatments at least three 
months before the start of the experiment. Water 
was freely available during all experimental 
courses. She-camels were fed on alfalfa hay 
according to the camel center feeding schemes. 
The ethics committee of King Faisal University (no. 
1811013) approved all experimental procedures 
and animal experiments. Waters Acquity Ultra-
high performance liquid chromatography Mass-
mass (UPLC–MS-MS) system equipped with an 
autosampler, C18 column, and Acquity Micromass 
triple-quadrupole was used to measure the serum 
concentration of injected Ceftiofur.
Drug administration
Ceftiofur-CAF 200 mg/ml suspension (Excede, 
Zoetis Inc, NJ, USA) sterile solution was injected 
i/m at a dose 6.6 mg/kg.
Collection of samples
Blood samples were collected from the left 
jugular vein in vacutainer tubes at 0, 0.13, 0.25, 
0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, and 144 hours 
after administration of the drug Administration. 
Blood samples were inverted briefly for three times 
and kept in insulated refrigerated boxes to clot. 
After 15 min, the tubes were centrifuged at room 
temperature at 2000 g for 15 min. Aliquots of 
serum were stored at - 80 °C until chromatographic 
analysis.
Sample preparation and extraction
The sample preparation was performed as 
described by (10, 11) with slight variations. A 
standard stock solution at different concentrations 
was prepared by dilution in MilliQ water starting 
from 150 to 3.125 ng/ml concentrations. Within 
this range, six different concentrations were used 
to plot the standard curve. All tubes were stored 
at - 30°C and melted just before the experiment.
Sample preparation included deproteinization, 
evaporation of the solvent, and final dissolving 
of the mobile phase. Serum was deproteinized 
in acetonitrile 1:7 (v/v). After vortexing, the 
denatured protein was removed by centrifugation 
for 13,000 rpm for 10 min. the supernatant was 
evaporated under a nitrogen stream and the pellet 
was redissolved in the mobile phase. Twenty 
microliters of the solution were injected into the 
UPLC–MS-MS system.
Chromatographic conditions
UPLC-MS/MS was performed using a Waters 
Acquity UPLC system (Waters Corp., MA, USA). 
The system is composed of Waters Acquity 
Micromass triple-quadrupole MS quadrupole 
with electrospray source, Waters Acquity BEH 
C18 column, autosampler, quaternary solvent 
management system. The system was operated 
under the control of MassLynx 4.1 software. The 
mass multi-reaction-monitoring (MRM) mode 
was as described previously (10, 12, 13). The 
running solution contained solution (A): UPLC 
grade water containing 0.1% formic acid, and 
solution (B): methanol containing 0.1% formic 
acid. Half mM ammonium acetate was added 
for both solutions A and B. The gradient elution 
program (14) comprised a gradual increase in 
97Pharmacokinetics of the long-acting ceftiofur crystalline-free acid in Arabian she-camels (Camelus dromedarius)
solution B until 85:15 (v/v). validations of runs and 
limits of detection quantification were performed 
as described previously  (15). The method was 
validated for selectivity, sensitivity, linearity, 
precision, accuracy, and stability. The blanc 
and drug samples were compared to assign the 
chromatographic selectivity. LLOQ (lower limit of 
quantification) was used as a measure of sensitivity 
by measuring the area of the curve that was at 
least five times higher than the blanc values. Drug 
concentrations of 0.195 ppb to 150 ppb were used 
for linearity checking. Intra and inter-day precision 
was carried out by measuring LLOQ, LOC, middle-
quality control (MQC), and high-quality control 
(HQC) levels. Accuracy was assigned by estimation 
of the amount extracted after the addition of known 
amounts of the drug. The chromatograms for LOD 
and LOQ are given in the supplementary materials 
(Supplementary files 1 and 2).
Pharmacokinetic analysis
The pharmacokinetic analysis was performed by 
nonlinear curve fitting analysis. The data were fitted 
with the aid of PKsolver Excel add-on software (16).
Results
Both non-compartment and compartment 
pharmacokinetic models were used to fit the 
obtained data. Fig.1 shows the relation between the 
serum concentrations of ceftiofur-CAF concerning 
time. The best-fitting was determined to be by a two-
compartment model to deliver the pharmacokinetic 
parameters (Table 1): α and β: the apparent rate 
constants of the distribution and elimination 
phases, the distribution and elimination half-lives 
(t1/2α and t1/2β), the rate constant for equilibration 
between the central and peripheral compartment 
(k12), return to the central compartment (k21), 
elimination from central component (k10) and the 
volume of distribution (V_F). The rate constant for 
distribution to the peripheral compartment was 
0.03 h-1 indicating slow transfer of drug from the 
central to peripheral compartment. The values of 
k12 and k21 indicate low and slow tissue penetration 
and a general preference for central compartment 
or serum. The area under the concentration curve 
(AUC 0-inf) was 354.1 μg/ml h-1 and mean residence 
time (MRT) 42.01 h.
Figure 1: The relation between the serum concentrations 
of ceftiofur-CAF concerning time. A) the concentration 
(Y-axis) is plotted against time (X-axis). The values 
of each she-camel are plotted separately. B) semi-
logarithmic plot of concentration-time relation. The 
values represent mean ± SD
98 M. Kandeel, W. El-Deeb, M. Fayez, I. Ghoneim
Table 1: Pharmacokinetic parameters of single i/m injection of 6.6 mg/kg of ceftiofur-CAF in she-camels (n = 3) 
Parameter Unit Average SD
A μg/ml 140.89 109.01
α 1/h 0.11 0.05
B μg/ml 5.77 4.39
β 1/h 0.02 0.01
ka 1/h 0.15 0.02
Parameter Unit Average SD
k10 1/h 0.05 0.01
k12 1/h 0.03 0.02
k21 1/h 0.05 0.04
t1/2α h 7.42 4.24
t1/2β h 46.13 37.75
t1/2ka h 4.64 0.75
V/F (mg/kg)/(μg/ml) 0.35 0.04
CL/F (mg/kg)/(μg/ml)/h 0.02 0.001
V2/F (mg/kg)/(μg/ml) 0.29 0.15
CL2/F (mg/kg)/(μg/ml)/h 0.01 0.01
Tmax h 9.41 1.35
Cmax μg/ml 9.29 0.42
AUC 0-t μg/ml*h 335.55 36.25
AUC 0-inf μg/ml*h 354.10 57.22
MRT h 42.01 15.64
Discussion
This study investigated the pharmacokinetics 
of ceftiofur long-acting preparation in camels. 
This will help in the design of a suitable dosing 
program. Hibbard et al. (2002) reported that a 
single s/c injection of ceftiofur-CAF produced 
plasma levels of ceftiofur remained above 0.2 
µg/ml for more than 7 days (7). In this study, 
ceftiofur-CAF injection in camels resulted in slow 
absorption from the injection site to reach a Cmax 
and Tmax of 9.41 μg/ml and 9.29 hours, respectively 
(Table 1). This indicates about 8 folds increase in 
the absorption time from the i/m injection site 
compared with immediate-release ceftiofur in 
camels, which was 1.22 h (17). Additionally, the 
Cmax of ceftiofur-CAF was 9.29, which is highly 
comparable to the previously reported Cmax of 
ceftiofur-IRF, 10.34 μg/ml (17).
The obtained Cmax in she-camels (9.29 μg/
ml) was prominently higher than 2.248 μg/ml in 
nonlactating goats (6), 1.458 in lactating goats 
(6), 6.39 μg/ml in beef cattle (6), 4.44 μg/ml in 
dairy cow, 2.45 μg/ml in sheep and 0.785 μg/
ml in equine (1). The s/c injection in dairy cows, 
sheep, and goats, compared with i/m injection 
in this study might affect the peak of serum 
concentration. However, the several folds higher 
serum concentration in camels suggests the 
delayed absorption and camel specific factors in 
ceftiofur disposition. The obtained Tmax in she-
camels (9.41 h) is to be described as an earlier 
peak of ceftiofur concentration compared with 
26.67 h in nonlactating goats (6) 46 h in lactating 
goats (6), 23 h in sheep (18), and 22 h in equine (1). 
The absorption half-life (t1/2βka) of ceftiofur-CAF 
in she-camels was 4.64 h, this is lower than the 
estimated value of 5.67 in nonlactating goats (6).
The distribution half-life (t1/2α) was 7.42 h 
indicating slow distribution. The t1/2α obtained 
in ceftiofur-IRF was recording less than 1 h in 
cattle, sheep, and goats and about 0.34 h in 
camels (17). Similarly, the estimated elimination 
half-life (t1/2β) was 46.13 h that is greatly higher 
than the average recorded value for ceftiofur-IRF, 
which was in the range of 3.18-5.83 h in cattle, 
99Pharmacokinetics of the long-acting ceftiofur crystalline-free acid in Arabian she-camels (Camelus dromedarius)
sheep, calves, or goats (17). Thus, ceftiofur-CAF 
produced a prominent long-lasting slow-release 
form in camels by showing delayed Tmax and 
longer distribution and elimination half-lives. The 
elimination half-life (t1/2β) of ceftiofur-CAF in she-
camels was 46.13 h, which is more or less similar 
to 47.31 h in nonlactating goats (6) and 100 h in 
equine (1). This implies species-specific differences 
in t1/2β in animal species. The administration of 
ceftiofur-IRF in domestic and exotic birds showed 
wide variability in pharmacokinetic parameters 
with Tmax = 0.83-2.67 h, Cmax = 0.86-10.99 μg/
ml, t1/2α = 0.28-3.8 h and t1/2β = 2.5-8.65 h (19). 
This indicates the wide variability of ceftiofur 
pharmacokinetics. 
The model for fitting ceftiofur-CAF pharmacok-
inetics was best explained by using a non-com-
partmental model in neonatal foals (3), equine (1), 
cattle egrets (9), guineafowl (20), American flamin-
gos (21), ball python (22), and Rhesus macaques 
(8), one-compartment model in sheep (18) and goat 
(6) and two-compartment model in swine (23). The 
present data were fitted by a two-compartment 
model. This model was used to fit the pharmacoki-
netics data in pigs injected with commercial ceftio-
fur HCl suspension at a dose rate of 5 mg/kg (23). 
Compared with pigs data, she-camels pharmacok-
inetic parameters showed a 6-folds increase in dis-
tribution half-live, 10.45-folds increase in absorp-
tion half-life, 5.9-folds increase in Tmax, 3.8 times 
lower Cmax, and 3.36-folds increase in elimination 
half-life. This indicates delayed absorption, distri-
bution, and elimination time in camels. Addition-
ally, the drug levels fall below the recommended 
level of 0.2 μg/ml in pigs in less than 96 h, com-
pared with 144 h in camels.
The analysis of the relation between the drug 
concentration and bacterial susceptibility was based 
on MIC levels for susceptible respiratory pathogens 
in cattle (7, 17). The obtained pharmacokinetic 
parameters revealed that one dose of i/m injection 
of ceftiofur-CAF at a dose rate of 6.6 mg/kg achieved 
serum levels above 0.2 μg/ml for 7 days in she-
camels. In our study, the concentration of ceftiofur 
remained above 0.2 μg/ml for an average time 
of 119.833 h. Moreover, for proper antibacterial 
efficiency, achieving serum concentrations about 
10-times the MIC values (24) or a serum level of 
2 μg/ml is required. Based on pharmacokinetic 
parameters, the level of ceftiofur falls below 2 μg/ml 
after 48 h of injection. Therefore, a single injection 
is sufficient to cover 7 days for highly susceptible 
bacteria and it is recommended to administer a 
second dose of ceftiofur-CAF after 2 days from the 
first injection for less susceptible bacteria. The 
estimated ceftiofur levels were above 0.2 μg/ml 
for 9.1 days in beef cattle (6.6 mg/kg), 6.7 days 
in nonlactating goats, 8.5 days in dairy cows, 
and 7.5 days in lactating goats (6). This indicates 
a shorter duration in she-camels compared 
with other animals. Taking into consideration 
the "flip-flop" pharmacokinetics of slow-release 
preparations, the terminal phase of elimination of 
the drug is complicated by its slow release from 
the injection site. However, the impact of "flip-flop" 
pharmacokinetics is underscored in this camel 
experiment, as the half-life of absorption (4.64 h) 
is much lower than the elimination half-life (t1/2β).
Conclusion: Ceftiofur-CAF achieved long-lasting 
serum levels in camels above the recommended 
level of 0.2 μg/ml for 4 days following a single i/m 
injection at a dose rate of 6.6 mg/kg. Careful dose 
adjustment depending on MIC values could be 
practiced by comparing its value with the provided 
concentration-time relation. Camels showed a 
higher peak of serum concentration with markers 
of slow excretion and longer persistence in the 
body compared with other animals.
Acknowledgments
The authors would like to acknowledge the 
Deanship of Scientific Research at King Faisal 
University for their financial support under the 
research group support track (grant no. 1811013).
The authors declare that they have no conflict 
of interest.
All animals' procedures were approved by 
the ethics committee of King Faisal University 
(approval no: 1811013). Informed consent not 
apply to this work.
Authors' contributions, MK, WE, and MF 
designed the experiment, MK, WE, MF, IG 
performed the experiment, MK, WE, MF analyzed 
the results, MK, WE, and MF wrote the manuscript, 
MK, WE, MF, IG approved the submission.
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(March, 2021)
FARMAKOKINETIKA DOLGODELUJOČE CEFTIOFURNE KRISTALINIČNE PROSTE KIS-
LINE PRI SAMICAH ARABSKIH KAMEL (Camelus dromedarius)
M. Kandeel, W. El-Deeb, M. Fayez, I. Ghoneim
Izvleček: Ceftiofur je pomemben širokospektralni antibiotik 3. generacije cefalosporinov. Zaradi njegovih časovno odvisnih 
protimikrobnih učinkov je čas, ko je raven ceftiofura nad bakterijskim MIC in ne pri njegovem vrhu koncentracije kritična točka 
pri uporabi tega antibiotika. Poskus je bil izveden z namenom ovrednotenja farmakokinetike dolgo delujoče ceftiofurjeve kri-
stalinične brezkislinske oblike (ceftiofur-CAF) pri kamelah. Ceftiofur-CAF v koncentraciji 200 mg/ml suspenzije sterilne raztopine 
smo injicirali i/m v odmerku 6,6 mg/kg. Vzorci krvi so bili zbrani iz vratne vene v vakuumskih epruvetah ob injiciranju antibiotika in 
nato 8, 15 in 30 minut po injiciranju ter 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 in 144 ur po injiciranju antibiotika. Za merjenje serumske kon-
centracije je bila uporabljena tekočinska kromatografija ultra visoke ločljivosti (UPLC MS/MS). Farmakokinetično modeliranje 
je bilo izvedeno z dvokomponentnim modelom. Farmakokinetiko ceftiofur-CAF-a po enkratnem i/m injiciranju v kamele je bilo 
najbolje modelirati v modelu z dvema predelkoma, kjer se je zdravilo počasi razdeljevalo v drugi predelek s slabo penetracijo v 
tkiva in veliko prednostjo do osrednjega predelka. Najvišja koncentracija antibiotika v plazmi (Cmax) je bila 9,29 ± 0,42 μg/ml pri 
T
max
 9,41 ± 1,35 ure. Površina pod krivuljo (AUC0-∞) je bila 354,1 ± 57,22 μg/ml*h. Razpolovni čas razporeditve in izločanja je bil 
7,42 oziroma 46,13 ure. Povprečni čas prisotnosti antibiotika (MRT) je bil 42,01 h. V primerjavi s hitro absorbirano obliko ceftiofurja 
(ceftiofur-RAF) pri kamelah je bila skoraj podobna največja koncentracija v serumu, vendar z zakasnjenim časom do največje 
koncentracije (T
max
), daljšim časom zadrževanja (MRT) in večjim razpolovnim časom porazdelitve in izločanja. Ceftiofur-CAF ostal 
dni nad predhodno priporočeno ravnijo učinkovitosti 0,2 μg/ml kar 7 dni, kar je bilo mogoče doseči po enkratni i/m injekciji 6,6 mg/
kg. Pridobljeni podatki o farmakokinetiki v kamelah priporočajo večkratno dajanje v razmaku 2 dni za bakterije, ki potrebujejo ravni 
MIC nad 2 μg/ml.
Ključne besede: Ceftiofur; farmakokinetika; kamela; cefalosporini