Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt

Pharmacokinetics, Urinary and Mammary Excretion of Ceftriaxone in Lactating

Goats

M. M. Ismail

Address of author: Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt;Tel: +20 1 0513 6201; E-mail: m_ism@hotmail.com

With 1 figure and 3 tables Received for publication December 17, 2003

Summary

The pharmacokinetic properties of ceftriaxone were investi-gated in 10 goats following a single intravenous (i.v.) and

intramuscular (i.m.) administration of 20 mg kg)1 bodyweight. After i.v. injection, ceftriaxone serum concentration–time curves were characteristic of a two-compartment open

model. The distribution and elimination half-lives (t1/2a, t1/2b)were 0.12 and 1.44 h respectively. Following i.m. injection,peak serum concentration (Cmax) of 23.6 lg ml)1 was attainedat 0.70 h. The absorption and elimination half-lives (t1/2ab,

t1/2el) were 0.138 and 1.65 h respectively. The systemic bio-availability of the i.m. administration (F %) was 85%. Fol-lowing i.v. and i.m. administration, the drug was excreted in

high concentrations in urine for 24 h post-administration. Thedrug was detected at low concentrations in milk of lactatinggoats. A recommended dosage of 20 mg kg)1 injected i.m.

every 12 h could be expected to provide a therapeutic serumconcentration exceeding the minimal inhibitory concentrationsfor different susceptible pathogens.

Introduction

Ceftriaxone is a 2-aminothiazoylmethoxyimino cephalospo-rin of the third generation. It has a broad-spectrum activity

against Gram-positive, Gram-negative and anaerobic bac-teria (Gnann et al., 1982; Rolf and Finegold, 1982). Theantibacterial activity against Gram-negative bacteria encom-

passes essentially all members of Enterobacteriaceae as wellas Pasteurella species. The drug acts through inhibition oftranspeptidase enzymes responsible for the final step in

bacterial cell wall synthesis (Waxam and Strominger, 1982)and has broad stability against beta-hydrolysis (Harold,1985). In addition, it is unique among other cephalosporinsin its low minimal inhibitory concentration (MIC)90 and

unusually long serum half-life in man (Delsignore et al.,1983). Despite the high cost of drugs of this group, their useis often cost-effective because of their excellent antibacterial

properties such as low minimal inhibitory concentra-tions (MICs) against Gram-negative bacteria and longhalf-life that allows to reduce dosing frequency to a two-

times daily.The pharmacokinetic properties of ceftriaxone have been

studied in various animal species (Hidefumi et al., 1984;

Soback and Ziv, 1988; Ringger et al., 1998). However, nodata is available for milk and urinary excretion of the drug indomestic animals as well as its disposition kinetics in goats.

The aim of this work was to investigate the pharmacokinetic

properties, milk concentrations and urine concentrations ofthe drug in goats to evaluate the possibilities of its use intreatment of bacterial diseases caused by Gram-negativebacteria, especially those resistant to other commonly used

antibiotics.

Materials and Methods

Animals

Ten clinically healthy non-pregnant goats, 2–2.5 years of ageand 25–30 kg body weight (b.w.) were used. Each goat washoused in an individual well-ventilated hygienic pen during the

entire period of the experiment. Animals were fed withantimicrobials free diet ad libitum with drinking water freelyavailable throughout the experimental period.

Experimental design

Ceftriaxone was obtained as sterile injectable powder (Roce-

phin�; Roche, Basel, Switzerland) and reconstituted in sterilesaline to a final concentration of 10% just prior to adminis-tration. In a cross-over design each of 10 goats was given a

single dose of 20 mg kg)1 b.w. of ceftriaxone through the leftjugular vein and an equal dose was injected intramuscularly(i.m.) to the same animals 2 weeks later.

Sampling

Blood samples (3 ml each) were collected from the rightjugular vein just before and at 5, 10, 15 and 30 min and 1, 2, 4,6, 8, 10, 12 and 24 h after dosing. Serum was left until clottingand separated by centrifugation at 1000 g for 20 min. Serum

was stored at )70�C until being analysed. Urine samples werecollected just before and after 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hof intravenous (i.v.) and i.m. administration of the drug by

using a rubber balloon catheter (19 f1 ch)1, Folatex, Norta).The bladder was emptied completely before administration ofthe drug and irrigated with 50 ml of potassium permanganate

solution 1:5000 after completion of urine sampling. The pH ofurine samples was determined throughout the entire samplingperiod by pH meter (Crison, Barcelona, Spain) (data notshown). Milk samples (5 ml from each udder half) were

collected at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h after i.v. and i.madministration of the drug. Urine and milk samples werestored at )20�C and assayed within 7 days of sampling.

U.S. Copyright Clearance Center Code Statement: 0931–184X/2005/5207–0354 $15.00/0 www.blackwell-synergy.com

J. Vet. Med. A 52, 354–358 (2005)

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Drug assay

Concentrations of ceftriaxone in serum, urine and milksamples were determined using a microbiological assaymethod with Micrococcus luteus ATCC 9341 serving as test

organism using Muller-Hinton agar medium (Bennet et al.,1966). Calibration curves were prepared by adding knownamounts (0.2, 0.4, 0.8, 1.6, 3.2, 6.4 and 12.8 lg ml)1) of

ceftriaxone to serum, milk and urine obtained from nontreated goats. Semi-logarithmic plots of the inhibition zoneversus standard ceftriaxone concentrations in serum, milk and

urine were subjected to linear regression analysis and concen-trations of the drug were determined using the intercept andslope of the regression line. Standard curves of ceftriaxonewere linear between 0.2–6.4 lg ml)1 in serum and milk and

0.2–12.8 lg ml)1 in urine. The correlation coefficients of thestandard curves were >0.97 for serum, >0.98 for milk and>0.99 for urine. Triplicates of each serum, milk and urine

sample as well as standard concentrations of the drug indifferent matrices (100 ll) were pipetted into individual wellsand the plates were incubated for 18 h at 37�C. The limit of

quantification in all samples was determined to be 0.2 lg ml)1.Intra-assay and interassay precision and accuracy were

estimated using each of the relevant matrices; serum, milk

and urine. Intra-assay precision and accuracy were determinedby measuring six replicates of each of three standard concen-trations (0.2, 0.8 and 3.2 lg ml)1) prepared in the relevantmatrices on the same gel. The intra-assay variation coefficients

were <3.4% for serum, <2.5% for milk and<3.9% for urine.Interassay precision and accuracy were determined by assayingthree standard concentrations prepared in the relevant matrices

on six occasions. The interassay variation coefficients were<4.2% for serum, <3.4% for milk and <4.6% for urine.

Serum protein-binding of the drug was estimated in vitro by

using antibiotic-free serum harvested from goats and phos-phate buffer (pH 8) according to the method of Craig and Suh(1980), which is based on the diffusion of the free antibioticinto the agar medium. To estimate the protein binding of

ceftriaxone, the drug was dissolved in phosphate buffer andantibiotic free goat’s serum at concentrations of 0.2, 0.8, 3.2and 12.8 lg ml)1 and tested in the microbiological assay as

mentioned above. The percentage of protein bound fractionwas calculated according to the following equation:

Protein binding percentage

¼ zone of inhibition in buffer-zone of inhibition in serum

zone of inhibition in buffer

� 100:

Pharmacokinetic analysis

A pharmacokinetic computer program (R Strip; Micromath

Scientific Software, Salt lake City, UT, USA) was used todetermine the least squares best-fit curve for ceftriaxoneconcentration versus time data. Choice of appropriate phar-

macokinetic model was constructed on the basis of the lowestweighted sum of squares and lowest Akaike’s informationcriterion value for the individual data (Yamaoka et al., 1978).

Following i.v. administration a two-compartment openmodel system (Baggot, 1978) was found to best fit the dataand suggested the use of the following biexponential equation:Ct ¼ Ae)at + Be)bt, where Ct is the serum concentration of

ceftriaxone; t is time after i.v. administration; A and a are theintercept and slope, respectively, of the distribution phase;B and b are the intercept and slope of the elimination phase;

e is the base of the natural logarithm. The distribution andelimination half lives (t1/2a and t1/2b), the volume of distri-bution at steady state (Vdss), the volume of the central

compartment (Vc), the total body clearance (ClB) and thetwo-compartment microconstants kel, k12, k21 were computedaccording to the standard equations (Gibaldi and Perrier,

1982). The serum concentrations followed by i.m. applicationwere analysed by non-compartmental method based on thestatistical moment theory (Yamaoka et al., 1978). The ter-minal elimination half-life (t1/2el) and absorption half-life

(t1/2ab) were calculated as ln 2/kel or ln 2/kab, respectively,where kel and kab are the elimination rate constant andabsorption rate constant respectively. The area under the

serum concentration–time curve (AUC0)¥) and area under themoment curve (AUMC) were calculated by the trapezoidalrule for all measured data with extrapolation to infinity using

Clast/b or Clast/kel, where Clast is the last serum concentrationreported divided by the b (elimination rate constant for two-compartment model) or kel in case of non-compartmental

analysis. The mean residence time (MRT) was calculated asMRT ¼ AUMC0)¥/AUC0)¥ and mean absorption time(MAT) as MAT ¼ MRTi.m ) MRTi.v.. The peak serum con-centration (Cmax) and time to maximum concentration (tmax)

were taken from the plot of each goat’s concentration–timecurve. Bioavailability (F) was calculated as follows:F ¼ AUCi.m/AUCi.v · 100.

Statistical analysis

The obtained results were displayed as mean ± SEM. Thestandard error of the mean was calculated according toSnedecor and Cochran (1976).

Results

Following i.v. administration of ceftriaxone, serum concentra-tion versus time curves of the drug decreased in a biphasic

manner, as characterized by a two-compartment open model.Figure 1 illustrates the mean serum concentrations as afunction of time. The pharmacokinetic parameters for ceftri-

axone followed by i.v. administration are summarized inTable 1. The distribution half-life (t1/2a) was 0.12 h andelimination half-life (t1/2b) was 1.44 h. The Vdss was 0.37 l kg)1.

Following i.m. administration, the mean serum con-centrations versus time curve (Fig. 1) was best fitted by a one-compartmentmodelwith first-order absorption. The absorptionhalf-life (t1/2ab) was 0.138 h and elimination half-life (t1/2b) was

1.65 h (Table 2). The maximum serum concentration of23.6 lg ml)1 was achieved at 0.7 h. The drug was detected inserum for 10 and 12 h following i.v and i.m. administration

respectively. The systemic F following i.m. route was 0.85.Binding tendency of ceftriaxone to serum protein of goats

ranged between 39% and 45% at therapeutic concentrations.

Ceftriaxone was detected in goats� urine for 24 h (Table 3)following i.v. and i.m. administration. The concentrations inurine ranged from 0.5 to 965.8 lg ml)1. The concentrations of

ceftriaxone in milk were low (Table 3) and within the range of0.26–16.8 lg ml)1.

Disposition Kinetics of Ceftriaxone in Goats 355

Discussion

The serum concentration versus time data curves obtainedafter i.v. administration of ceftriaxone at a dose rate of

20 mg kg)1 in goats showed a biphasic decline. The drug was

rapidly distributed with a distribution half-life (t1/2a) of 0.12 h.This value was similar to the value reported in dogs byHidefumi et al. (1984). The elimination half-life was 1.44 h,

this value is similar to that reported in sheep given a dose of47 mg kg)1 (Guerrini et al., 1985). It is close to those obtainedby other investigators in calves, 1.7 h (Soback and Ziv, 1988),horses, 1.6 h (Ringger et al., 1996) and pigs, 1.1 h (Cavalier

et al., 1997). But it was lower to the values reported in humans(6.1 h) and neonatal foals (3.25 h) (Pollock et al., 1982;Ringger et al., 1998).

Tozer (1981) stated that cephalosporins with high a proteinbinding have a small volume of distribution compared withthose with low protein binding. Our results suggested that

ceftriaxone has a small volume of distribution Vdss

(0.37 l kg)1), this value was close to those reported in otheranimal species including sheep and calves (0.29 l kg)1;

Guerrini et al., 1985; Soback and Ziv, 1988). Compared withhuman beings, the reported Vdss in goats is about three timesthe values (0.13–0.18 l kg)1) reported in humans (Patel et al.,1981; McNamara et al., 1982). The relatively higher value in

the volume of distribution in goats is clinically advantageous.The reported total body clearance (ClB) in goats(3.95 ml min)1 kg)1) is very similar to those reported in sheep

and calves (3.38 and 3.19 ml min)1 kg)1) respectively(Guerrini et al., 1985; Soback and Ziv, 1988).

Following i.m. administration of ceftriaxone, the drug was

rapidly absorbed with t1/2ab of 0.138 h. The t1/2el (1.65 h)followed by i.m. administration was longer than the t1/2bfollowed by i.v. administration. The reported value was closeto the values reported in sheep (1.7 h) and calves (1.9 h)

(Guerrini et al., 1985; Soback and Ziv, 1988). The reportedvalues (6.7 and 8.9 h) in humans were remarkably higher(Pickup et al., 1981; Delsignore et al., 1983). The higher

protein binding of ceftriaxone in humans could explain suchdifference. The average MAT (0.65 h) was approximately halfof the MRTi.v. (1.56 h) and 25% of the MRTi.m value. The

value of systemic bioavailability (85%) indicates almostcomplete absorption of the drug from i.m. injection site. Thisvalue is very close to that reported for calves (82%) by Soback

and Ziv (1988).Normally, the aim of a therapy with beta-lactam antibiotics

is to keep the serum concentration above the MICs at whichbacteria are eliminated (time-dependant killing) (Bergeron,

1992; Craig, 1993). Ceftriaxone has a MIC90 of £0.78 lg ml)1

for the following human pathogens: Escherichia coli, Klebsiella

0.1

1

10

100

1000

0 2 4 6 8 10 12Time (h)

Seru

m c

once

ntra

tions

(µg

ml–1

)

i.m. i.v.

Fig. 1. Semi-logarithmic graphdepicting the time–concentrationcourse of ceftriaxone in lactatinggoats following intravenous andintramuscular administration of20 mg kg)1 body weight (n ¼ 10).

Table 1. Pharmacokinetic parameters (mean ± SEM) of ceftriaxonein goats following intravenous (i.v.) administration of 20 mg kg)1

(n ¼ 10)

Parameters Mean ± SEM Unit

Cp� 160.7 ± 11.6 lg ml)1

B 29.39 ± 1.3 lg ml)1

b 0.48 ± 0.03 h)1

t1/2b 1.44 ± 0.01 hA 131.3 ± 10.5 lg ml)1

a 5.69 ± 0.41 h)1

t1/2a 0.121 ± 0.009 hK12 2.83 ± 0.16 h)1

K21 1.43 ± 0.1 h)1

Kel 1.9 ± 0.09 h)1

Vc 0.124 ± 0.008 l kg)1

Vdss 0.37 ± 0.019 l kg)1

ClB 3.95 ± 0.25 ml min)1 kg)1

MRT 1.56 ± 0.11 hAUMC 131 ± 5.4 lg h2 ml)1

AUCi.v. 84.2 ± 6.3 lg h ml)1

MRT, mean residence time; AUMC, area under the moment curve;AUC, area under the curve.

Table 2. Pharmacokinetic parameters (mean ± SEM) of ceftriaxonein goats following intramuscular (i.m.) administration of 20 mg kg)1

(n ¼ 10)

Parameters Mean ± SEM Unit

Kab 4.99 ± 0.26 h)1

t1/2(ab) 0.138 ± 0.009 hKel 0.419 ± 0.02 h)1

t1/2el 1.65 ± 0.009 hCmax 23.6 ± 1.2 lg ml)1

tmax 0.7 ± 0.12 hMRT 2.21 ± 0.13 hMAT 0.65 ± 0.03 hAUMC 159 ± 6.8 lg h2 ml)1

AUC 71.68 ± 3.4 lg h ml)1

F 85 ± 6.4 %

MRT, mean residence time; MAT, mean absorption time; AUMC,area under the moment curve; AUC, area under the curve.

356 M. M. Ismail

sp. and Salmonella sp. (Scheld et al., 1984). For 198 strains of

Salmonella, E. coli and Pasteurella multocida (0.03–0.2 lg ml)1) isolated from calves the MIC90 were even lower(Soback and Ziv, 1988). Our results indicate that the serum

concentration (0.27 lg ml)1) of ceftriaxone 12 h post-i.m.administration was exceeding the MIC90 (0.2 lg ml)1) valuesfor isolates of Salmonella sp., E. coli and P. multocida from

calves. Therefore, ceftriaxone may prove to be used at a doseof 20 mg kg)1 twice daily in the treatment of bacterial diseasesin goats caused by susceptible Gram-negative pathogensespecially those caused by micro-organisms resistant to the

other commonly used antimicrobials such as gentamicin,doxycycline, oxytetracycline and trimethoprim–sulphameth-oxazole (Singh et al., 1992).

The role that serum protein-binding plays in limiting tissuedrug concentration and antibacterial efficiency in vivo iscontroversial (Wise, 1985). Protein binding (39–45%) in this

study was significantly lower than in humans (87–96%)(Seddon et al., 1980; Stoeckel et al., 1981). Low proteinbinding (20–36%) for ceftriaxone has been also reported for

calves (Soback and Ziv, 1988). The variation in proteinbinding of ceftriaxone in different species could be attributedto the presence of two-binding sites on the serum albumin ofman whereas, only one-binding site has been detected in horses

(Popick et al., 1987). Moreover, affinity of the drug to bind tothese sites may vary between species. The low protein bindingin goats and calves is of therapeutic advantage, as it guarantees

a rapid penetration of the drug into different tissues.The prevalence of different bacterial species as causative

agents for caprine mastitis has been studied previously, and

coagulase-negative staphylococci, Staphylococcus aureus,Streptococcus sp. and E. coli are apparently the main patho-gens in goats (Verheijden et al., 1983; Poutrel, 1984; Manser,1986; East et al., 1987; Foschino et al., 2002; Bergonier et al.,

2003). The in vitro MIC90 values for ceftriaxone were 0.1–0.2 lg ml)1 for streptococci and coagulase negative staphylo-cocci and 0.03–0.06 lg ml)1 for coliform bacteria, which

indicates excellent activity of the drug against the mainpathogens responsible for mastitis in goats. As a result of itsacidic nature (pKa 4.3), ceftriaxone is detected at rather low

concentrations in goats� milk (serum/milk ratio; 1.5–4.4).Nevertheless, even these low concentrations are exceeding thepreviously mentioned MICs for 8 and 10 h post-i.v. and i.m.

injections respectively. The elevated pH (6.9–7.2) of mastiticmilk as well as the reduced integrity of blood–milk barrier

during mastitis (Prescott et al., 2000) could also play a

significant role in enhancing the penetration of ceftriaxoneinto the mastitic milk. These findings indicate that the use ofceftriaxone in treatment of caprine mastitis, especially in cases

of mixed infections involving Gram-negative and Gram-positive bacteria, or in cases of systemic infection (bacterae-mia) can be beneficial.

Ceftriaxone could also be detected in goats’ urine in highconcentrations up to 24 h post-i.v. and i.m. administration.The urine concentrations of the drug were exceeding the MICs(0.1–0.3) of Gram-negative bacteria, mainly E. coli, respon-

sible for urinary tract infections in goats (Blood et al., 1979;Singh et al., 1992). These findings indicate that ceftriaxonewould be efficacious in the treatment of urinary tract infections

caused by susceptible pathogens in goats when administeredi.v. or i.m. at a single daily dose of 20 mg kg)1 b.w.

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