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Iranian Journal of Veterinary Research, University of Shiraz, Vol. 8, No. 2, Ser. No. 19, 2007 Pharmacokinetics of tetracycline hydrochloride
in fat-tailed sheep
Rajaian, H.1* and Soleimani Mohammadi, E.2

1Department of Pharmacology, School of Veterinary Medicine, University of Shiraz, Shiraz, Iran; 2Graduated
from School of Veterinary Medicine, Islamic Azad University of Shahrekord, Shahrekord, Iran
*Correspondence: H. Rajaian, Department of Pharmacology, School of Veterinary Medicine, University of
Shiraz, Shiraz, Iran. E-mail: [email protected]
(Received 25 Jul 2005; revised version 8 Nov 2005; accepted 8 Jan 2006) Tetracycline may be used to treat several types of bacterial diseases in ruminants. In addition, tetracycline is added to food to promote the growth. There are few reports on the pharmacokinetics of tetracycline in sheep. Therefore, the objective of this study was to examine the pharmacokinetic characteristics of the drug in sheep. Ten apparently healthy mixed-breed sheep were administered 20 mg/kg tetracycline orally and intravenously with a time interval of two weeks. Blood samples were collected before and at various time intervals after the administration of the drug. Sera were separated, kept at -20°C, and analysed using fluorescence spectrophotometry. The volume of distribution (Vd), elimination rate constant (Kel), half-life (t1/2), and clearance (ClB) of tetracycline after intravenous injection were determined to be 0.21 L/kg, 0.21/hr, 3.3 hr, and 0.73 ml/kg/min, respectively. When the drug was given orally, these parameters
were found to be 0.37 L/kg, 0.12/hr, 5.8 hr, and 0.73 ml/kg/min, respectively. Moreover, the bioavailability
of tetracycline after oral administration was around 55%.
Key words: Tetracycline, Pharmacokinetics, Sheep
Introduction
Ziv and Sulman, 1974; Bradley et al., 1982; Xia et al., 1983a; Nouws et al., 1985; Riond et al., 1989; Meijer et al., 1993), sheep (Ziv 1986), goats (Jha et al., 1989; Escudero et al., 1994; Escudero et al., 1996), pigs (Xia et al., 1983b; Hall et al., 1989), dogs (Baggot drug was first introduced for clinical use in et al., 1977; Wilson et al., 1985) and horses 1952 and is still used both in small and food- (Pilloud, 1973; Teske et al., 1973; Horspool producing animals. Tetracyclines have been and McKellar, 1990). Relatively little has used in ruminants as both prophylactic and ruminants. The objective of this study was to characteristics of tetracycline in sheep after susceptibility to the drug but also of the a single oral or intravenous dose of the drug. achieved in the animal’s body fluids. Drug Materials and Methods
pharmacokinetics of tetracycline in different animal species such as cattle (Pilloud, 1973; had access to water and food ad libitum.
Iranian Journal of Veterinary Research, University of Shiraz, Vol. 8, No. 2, Ser. No. 19, 2007
Drug
Pharmacokinetic analysis
1- Single intravenous dose: The blood pooled from the available drug dosage form concentration-time data were analysed by non-linear least squares regression analysis Iran). The volume of antibiotic solution— (Fig. 1a). A non-compartmental analysis was found to be appropriate to estimate the major administered to each animal was calculated pharmacokinetic parameters. Area under the based on the body weight and a correction concentration-time curve from time zero to factor for the purity of the drug solution trapezoidal rule with extrapolation to infinite hydrochloride solution (Merck Co., Lot No. time by dividing the last available blood disposition rate constant; the apparent first- Experimental design
order rate constant for elimination (Kel) was In a cross-over design, five sheep were phase of the log concentration-time data. chloride intravenously through the right The elimination half-life (t1/2) was calculated jugular vein. Another five sheep were given the drug at the same dose orally. After a administration, the groups were switched. Blood samples were collected from the left jugular vein on -5, 5, 15, 30 and 60 min, and intravenous injection of tetracycline. For the a) Intravenous dose
oral route, blood samples were taken on -5, 1, 2.5, 3.5, 4.5, 7, 9, 13, 17 and 24 hrs after administration of the antibiotic. Sera were separated by centrifugation at 1500 g for 15 min and stored at -20°C until drug analysis Tetracycline assay
Time (hrs)
metry (Chang et al., 1992). In summary, serum proteins were first precipitated by b) Oral dose
addition of tricarboxylic acid solution. Then 0.3 M potassium hydroxide (2 ml) solution serum samples or standards. After vortex, tubes were kept in boiling water bath for 30 adjusted to 10 ml by addition of distilled water. The fluorescence of each sample and standards were determined by fluorescence Scientific Instruments) at excitation and emission wavelengths of 333 and 450 nm, respectively. The mean ± SEM recovery of Time (hrs)
tetracycline was 87.4 ± 3.2 (n=5; CV<10%).
Fig. 1: Log blood concentration-time plot for
The sensitivity of the test was >2 µg/ml. tetracycline (20 mg/kg) administered to sheep
Iranian Journal of Veterinary Research, University of Shiraz, Vol. 8, No. 2, Ser. No. 19, 2007 administration of tetracycline (Fig. 1b) was best described by a one-compartment model with first-order input (absorption). The greater than its corresponding mean value fraction of dose absorbed (F) was estimated (P≤0.05). The apparent Vd of tetracycline in intravenous administration of the drug. Kel sheep was found to be 0.37 L/kg; and ClB was obtained from the slope of the log-linear portion of the elimination phase of serum Table 1: Disposition kinetics in sheep given a
were calculated as described earlier and single oral or intravenous dose of tetracycline
hydrochloride (20 mg/kg)
Statistical analysis
Means were compared by Student’s t-test for independent samples. The F-test was used to determine which compartmental model best described the kinetics of tetracycline in AUC (area under the serum concentration versus Intravenous dose
After intravenous injection of 20 mg/kg distribution); Kel (elimination rate constant); t1/2 tetracycline hydrochloride, an initial concen- (elimination half-life); ClB (clearance) tration of 200 µg/ml was attained in serum. Six hrs later, the concentration decreased to Discussion
one-tenth of its initial level, i.e., to almost 20 µg/ml. The mean log blood concentration- The serum concentrations of tetracycline time plot (Fig. 1a) for tetracycline was non- in sheep were proportionally similar to those linear after intravenous administration of the obtained for doxycycline and minocycline in drug; the disappearance of the drug from with a rapid distribution phase (t1/2 <0.5 hr) tetracycline, administered intravenously to followed by a slow elimination phase (t1/2 ≈ distribution of tetracycline was 0.21 L/kg. described for cows and chickens (Ziv and The blood clearance of tetracycline in sheep was found to be 0.73 ml/min/kg (Table 1). Oral dose
Varma and Paul, 1983). However, marked (251 µg hr/ml) with that of intravenous dose pharmacokinetic parameters for tetracycline availability (F) of the drug was almost 55%. After oral administration of tetracycline, Two hrs following oral administration of the the drug concentration decreased to less than 3 µg/ml after 24 hrs. Bearing in mind that the antimicrobial activity of tetracycline in attained. The maximum blood concentration (Cmax) was almost 22 µg/ml that was attained concentrations >0.5 µg/ml (Pijpers et al., almost four hrs after drug administration (Tmax = 4 hrs). The decline in tetracycline possibly be attainable with administration of Iranian Journal of Veterinary Research, University of Shiraz, Vol. 8, No. 2, Ser. No. 19, 2007 problem of change in the rumen flora should Table 2 illustrates the pharmacokinetic intravenous injection, may indicate that diffusion of tetracycline out of blood vessels tetracycline after intravenous injection of the is poor. The apparent Vd after oral adminis- drug in sheep is almost five times less than tration of tetracycline was more than that the value found in rabbits (Percy and Black, after intravenous route (0.37 vs 0.21 L/kg, 1988). It is, however, similar to the value reported for chickens (Anadon et al., 1985). intestinal tissues and antibiotic adsorption to doxycycline in goats (Jha et al., 1989; Table the food contents, particularly of the rumen. The drug elimination t1/2 for tetracycline tetracycline t1/2 and Kel indicates that the in sheep is close to those values reported for drug is eliminated at a slower rate when Paul, 1983), chlortetracycline in cows and (Table 1). This difference in part can be due ewes (Ziv and Sulman, 1974), tetracycline in to the durable nature of the drug absorption pigs (Kniffen et al., 1989) and minocycline Furthermore, the longest t1/2 (around17 hrs) poorly studied in animal species, particularly is reported for doxycycline in goats (Jha et al., 1989); the shortest t1/2 (2 hrs) belongs to examined the disposition of tetracycline in tetracycline in rabbits (Percy and Black, some species, though, numerous reports are available on other members of tetracyclines. similar to that in horses for oxytetracycline (Horspool and McKellar, 1990). The largest intravenous administration of the drug to clearance is reported for oxytetracycline in sheep will remain more than 3 µg/ml for at least 12 hrs. The t1/2 of tetracycline was also reported to be 11.2 hrs—almost three times between the pharmacokinetic properties of
Table 2: Pharmacokinetics of tetracyclines following intravenous administration in different animals
*Vd (apparent volume of distribution); †Kel (elimination rate constant); ‡t1/2 (elimination half-life); §ClB Iranian Journal of Veterinary Research, University of Shiraz, Vol. 8, No. 2, Ser. No. 19, 2007 tetracyclines in sheep and other domestic administration. Equine Vet. J., 22: 284-285. animals indicate the importance of pharma- cokinetic studies for establishing a correct Singh, SD (1989). Pharmacokinetics data on doxycycline and its distribution in different biological fluids in female goats. Vet. Res. Commun., 13: 11-16. Acknowledgements
Kniffen, TS; Bane, DP; Hall, WF; Koritz, GD pharmacokinetics, and plasma concentration Mr. Jalaee for his technical assistance. of tetracycline hydrochloride fed to swine. Financial support by Shiraz University and Islamic Azad University of Shahrekord is Laczay, P; Semjen, G; Lehel, J and Nagy, G (2001). Pharmacokinetics and bioavailability of doxycycline in fasted and non-fasted broiler chickens. Acta Vet. Hung., 49: 31-37. References
Meijer, LA; Ceyssens, KGF; Dejong, WTH and Anadon, A; Martinez-Larranaga, MR and Diaz, elimination of oxytetracycline in veal calves: MJ (1985). Pharmacokinetics of tetracycline in chickens after intravenous administration. elimination phase. J. Vet. Pharmacol. Ther., Baggot, JD; Powers, TE; Kowajaski, JJ and Kerr, Nouws, JFM; Smulders, A and Rappalini, M KM (1977). Pharmacokinetics and dosage of (1985). Comparative pharmacokinetics and oxytetracycline in dogs. Res. Vet. Sci., 24: oxytetracycline-10% formulations in dairy Bradley, BD; Allen, EH; Showalter, DH and pharmacokinetics of chlortetracycline in milk-fed versus conventionally fed calves. J. domestic rabbit following intravenous or oral administration. Can. J. Vet. Res., 52: 5-11. Pijpers, A; Schoevers, EJ; Van Gogh, H; Van (1992). Spectrofluorimetric determination of tetracycline and anhydrotetracycline in serum oxytetracycline in the turkey: evaluation of healthy and diseased pigs. J. Vet. Pharmacol. biliary and urinary excretion. Am. J. Vet. Pilloud, M (1973). Pharmacokinetics, plasma Escudero, E; Carceles, CM and Serrano, JM protein binding and dosage of oxytetracycline (1994). Pharmacokinetics of oxytetracycline in cattle and horses. Res. Vet. Sci., 15: 224- in goats: modifications induced by a long- acting formulation. Vet. Rec., 135: 548-552. Riond, JL; Tyczkowska, K and Riviere, JE Escudero, E; Carceles, CM; Ponferrada, C and Baggot, JD (1996). Pharmacokinetics of a long-acting formulation of oxytetracycline in mature or immature rumen function. Am. J. sheep and goats. J. Vet. Pharmacol. Ther., 19: Riviere, JE and Spoo, JW (1995). Tetracycline antibiotics. In: Adams, RH (Ed.), Veterinary pharmacology and therapeutics. (7th. Edn.), Ames, Iowa, Iowa State University Press. PP: Hall, WF; Kniffen, TS; Bane, DP; Bevill, RF and Koritz, GD (1989). Plasma concentrations of Teske, RH; Rollins, LD; Condon, RJ and Carter, oxytetracycline in swine after administration of the drug intramuscularly and orally in intravenous and intramuscular administration feed. J. Am. Vet. Med. Assoc., 194: 1265- in horses. J. Am. Vet. Med. Assoc., 162: 119- Disposition of oxytetracycline in horses, Pharmacokinetics and plasma protein binding (in vitro) of oxytetracycline in buffalo Iranian Journal of Veterinary Research, University of Shiraz, Vol. 8, No. 2, Ser. No. 19, 2007 (Bubalus bubalis). Am. J. Vet. Res., 44: 497- Xia, W; Neilsen, P and Gyrd-Hensen, N (1983a). Comparison of pharmacokinetic parameters for two oxytetracycline preparations in cows. Xia, W; Gyrd-Hensen, N and Neilsen, P (1983b). hypoproteinemic sheep. Am. J. Vet. Res., 47: Comparison of pharmacokinetic parameters for two oxytetracycline preparations in pigs. Ziv, G and Sulman, FG (1974). Analysis of non-compartmental pharmacokinetic analyses of minocycline hydrochloride in the dog. Am. tetracycline analogues in dairy cows and

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