Characterization of the relationship between serum and milk residue disposition of ceftriaxone in lactating ewes

Abstract

The present study was planned to investigate the serum disposition kinetics and the pattern of ceftriaxone elimination in milk and urine of lactating ewes (n = 6) following i.v. and i.m. administration. A crossover study was carried out in two phases separated by 15 days. Ceftriaxone was administered at a dosage of 10 mg/kg b.w. in all animals. Serum, milk and urine samples were collected between 0 and 72 h and a modified agar diffusion bioassay method was used to determine the percentage of protein binding and to measure serum, urine and milk concentrations of ceftriaxone. The drug was detected between 5 min and 48 h postdosing. Concentrations of 0.56 (10 h) and 0.52 (12 h), 0.22 (10 h) and 0.19 (12 h), and 2.18 (24 h) and 2.11 (48 h) mug/mL were measured in serum, milk and urine following i.v. and i.m. administration, respectively. Individual pharmacokinetic parameters were determined by fitting a two-compartment model to the serum and one-compartment open model to the milk concentration-time profiles. After i.v. dosing, the elimination rate constant and elimination half-life were 0.4 +/- 0.05/h and 1.75 +/- 0.02 h, respectively. The volume of distribution at steady state (V(dss)) of 0.28 +/- 0.15 L/kg reflected limited extracellular distribution of the drug with total body clearance (Cl(tot)) of 0.14 +/- 0.10 L/h/kg. Following i.m. administration, the mean T(max obs), C(max obs), t(1/2el) and AUC values for serum data were: 0.75 h, 23.16 +/- 2.94 microg/mL, 1.77 +/- 0.24 h and 67.55 +/- 6.51 microgxh/mL, respectively. For milk the data were: 1.0 h, 8.15 +/- 0.71 mug/mL, 2.2 +/- 0.34 h and 26.6 +/- 5.14 microgxh/mL, respectively. The i.m. bioavailability was 83.6% and the binding percentage of ceftriaxone to serum protein was 33%. Concentrations of ceftriaxone in milk produced by clinically normal mammary glands of ewes were consistently lower than in serum; the kinetic value AUC(milk)/AUC(serum) and C(max milk)/C(max serum) ratios was<0.4. These low values indicated poor distribution and penetration of ceftriaxone from the bloodstream to the mammary gland of lactating ewes following both routes.

Comparative pharmacokinetics of intravenous cephalexin in pregnant, lactating, and nonpregnant, nonlactating goats

“…, 1990). A previous report characterizing the pharmacokinetics of ceftriaxone in lactating ewes found that the kinetic parameters calculated for the lactating animals were similar to those recorded in a previous report for nonlactating sheep (Goudah et al. , 2006).…”

Plasma pharmacokinetics and milk levels of ceftriaxone following single intravenous administration in healthy and endometritic cows

“…The calculated value for apparent volume of distribution of ceftriaxone (0.5±0.19 L.kg −1 ) in healthy cows indicated moderate distribution of the drug. In agreement to the present results, lower values of Vd area have been reported for ceftriaxone in ewes (0.28 L.kg −1 ), camel (0.32 L.kg −1 ) and goats (0.28-0.58 L.kg −1 ) after intravenous administration (Goudah et al 2006;Sar et al 2006;Goudah 2008;Tiwari et al 2009). However, large Vd area has also been Cp 0 = plasma drug concentration at time zero of intravenous dosing; α 1 and α 2 = distribution rate constants from central to peripheral compartments; β = elimination rate constant; t 1/2 α 1 and t 1/2 α 2 = distribution half lives of the two distribution phases; t 1/2 β = elimination half life; K 12 , K 13 , K 21 and K 31 = rate constants of drug transfer from central to peripheral compartments and vice-versa; AUC = area under the plasmaconcentration time curve; AUMC = area under the first moment of plasma-concentration time curve; Vd (area) = apparent volume of distribution; Cl B = total body clearance of drug; K el = rate constant for elimination of drug from central compartment; MRT = mean residence time; P/C = ratio of drug present in peripheral to central compartment reported for ceftriaxone in calves (1.91 L.kg −1 ) and buffalo calves (1.4 L.kg −1 ) following intravenous administration (Johal and Srivastava 1999;Dardi et al 2004).…”

“…Lower value of AUC of ceftriaxone in endometritic cows (37.0±17.1 μg.ml −1 .h) in comparison to its corresponding value in healthy cows reflected a smaller area covered under drug concentration during endometritis in animals. The short elimination half-life of ceftriaxone in healthy cows (1.02±0.07 h) was comparable to the t ½β of 1.5 h in goats, 1.75 h in ewes, 1.27 h in buffalo calves, 0.81 h in mares and 83.8 min in neonate calves (Soback and Ziv 1988;Gardner and Aucoin 1994;Goudah et al 2006;Gohil et al 2009;Tiwari et al 2009), however it was shorter than the t ½β of 4.39± 0.63 h in calves and 2.57 h in camels (Johal and Srivastava 1999;Goudah 2008) after intravenous injection of ceftriaxone. The average mean residence time of ceftriaxone in healthy cows observed in the present study was 1.55±0.25 h. Similar low values have been reported for the MRT of ceftriaxone in goats (1.01 h), buffalo calves (1.34 h), ewes (1.93 h) and neonatal calves (1.57 h) following its intravenous dosing (Soback and Ziv 1988;Goudah et al 2006;Gohil et al 2009;Tiwari et al 2009).…”

“…No drug could be detected in milk of both healthy and endometritic cows after 48 h of dosing. On the contrary, lower concentrations of ceftriaxone have been reported in ewes (0.22 μg.ml −1 ) at 10 h following intravenous dose of 10 mg.kg −1 and in goats (33.3 μg.ml −1 ) at 3 h after intravenous dose of 50 mg.kg −1 (Goudah et al 2006;Sar et al 2006). Taking 6 h as a dosage interval (τ), with a minimum therapeutic plasma level (Cp min ∝ ) of 0.5 μg.ml −1 and using the values of β and Vd area of healthy cows from Table 1, the priming and maintenance doses of ceftriaxone were calculated as 10.7 and 10.4 mg.kg −1 , respectively The dosage interval was shorter than 12 and 24 h dosing interval suggested for the same doses of ceftriaxone in calves and buffalo calves, respectively (Johal and Srivastava 1999;Dardi et al 2004).…”

“…The presence of drug residues in milk may have public health implications, and is perceived by consumers as undesirable, therefore knowledge about the penetration of ceftriaxone from blood to milk is worth consideration (Goudah et al 2006). Disposition kinetics of ceftriaxone has been conducted in calves (Johal and Srivastava 1999;Soback and Ziv 1988), buffalo calves (Dardi et al 2004(Dardi et al , 2005(Dardi et al , 2007Gohil et al 2009), sheep (Guerrini et al 1988;Goudah et al 2006), goats (Sar et al 2006;Tiwari et al 2009) and camel (Goudah 2008). However, information on the pharmacokinetics of ceftriaxone in cattle species under endometritic condition is meager.…”