Pharmacokinetic interaction of tulathromycin with Flunixin meglumine after intravenous injection in goats

ARTICLE INFO The pharmacokinetic aspects of tulathromycin (2.5 mg/kg b.w.) were studied following intravenous administration alone and in combination with flunixin meglumine (2.2 mg/kg b.w) in apparently healthy goats. Tulathromycin concentrations in serum were determined by microbiological assay technique using Bacillus subtiles (ATCC 66343) as test organism. The half-lives of distribution and elimination (t 0.5(α)and t 0.5(β)) were 0.071, 0.046 and 6.43, and 5.05 h. following intravenous injection of tulathromycin alone and in combination with flunixin, respectively. Volume of distribution at steady state (Vdss) was 0.249 and 0.96l/kg., mean residence time (MRT) was 6.27 and 5.99 h and total body clearance (ClB) was 0.046 and 0.17 l/kg/hr., respectively. It was concluded that flunixin significantly altered the pharmacokinetics of tulathromycin by increase its distribution and accelerate its elimination from body. Therefore care should be taken during use of tulathromycin in goats concurrently with flunixin. Article history:


Introduction
Tulathromycin is a novel triamilide antimicrobial in the macrolide class shown to be safe and effective in cattle and swine to treat bacterial respiratory disease (Benchaoui et al., 2004;Nowakowski et al., 2004;Evans, 2005). Macrolide structure facilitates rapid distribution of these drugs from the blood stream into tissues (Williams &Sefton, 1993). Newer macrolides, such as azithromycin and tulathromycin, have increased lung tissue uptake and longer half-lives than older macrolides such as erythromycin (Benchaoui et al., 2004). In addition, the tripleionized form of tulathromycin produces displacement of the Mg 2+ ions present in the outer cell gram wall of -negative bacterial drug entry into pathogens, facilitating these agents ( Nutsch et al., 2005;Godinho et al., 2005;Skogerboe etal., 2005 andRobb et al., 2007).
Non steroidal anti-inflammatory of inhibitors are drugs (NSAIDs) cyclooxygenase that catalyze the incorporation of molecular oxygen into arachidonic acid to produce prostanoids (eg, thromboxanes, prostacyclin, and prostaglandin) and are effectively administered for inflammation and pain. Flunixin is one of (NSAIDs) has been reported to reduce fevers and improve clinical signs of endotoxemia (Anderson et al., 1986). Flunixin has been widely used for their anti-inflammatory and analgesic prosperities to treat the musculoskeletal conditions and colic in equine. It was also used routinely in ruminant practice to treat mastitis, endotoxemia and pneumonia (Zu-Gong et al., 2007). It is well documented that concurrent administration of drugs together may alter the pharmacokinetic parameters of these drugs. In veterinary practice the administration of antibiotics and NSAIDs at the same time was more common. Therefore, the aim of the study was to compare the disposition kinetic of tulathromycin in goats after a single alone and intravenous administration flunixin with when administrated meglumine.

Material and Methods
Drugs: Tulathromycin 100 mg ml -1 was solution an injectable supplied as division health (Draxxin®) by animal Egypt.
Animals: Ten apparently healthy, male and female Egyptian goats (3-9 months old and mean body weight of (12-23 kg) were used. Animals were obtained from a local market at Beni-Suef province, kept under good hygienic condition, fed barseem and free access to water.

Methods:
Experimental design: The animals were randomly divided into two groups (five goats each). Animals of first group were injected intravenously with tulathromycin in alone single dose of 2.5 mg kg -1 et al. Standard tulathromycin concentrations of 0.078, 0.156, 0.3125, 0.625, 1.25, 2.5, 5, 10 and 20 µg ml -1 were prepared in antibiotic-free goat serum and phosphate buffer saline (pH 8). The assay the minimal detectable limit for method was . 0.078 µg ml -1 Semilogarithmic plots of the inhibition zone diameter versus standard tulathromycin concentrations in serum and phosphate buffer were linear with typical correlation coefficient of 0.992 (for the standard curve).

Pharmacokinetic analysis:
A computerized curve stripping program (R Strip; Micromath Scientific Software, Salt Lake City, UT, USA) was used to analyze the serum concentration-time curves for each individual animal using theory moment the statistical (Gibaldi 1982) and Perrier, . Following IV injection, the serum concentration-time relationship was best estimated as a twocompartment open model system (Baggot, 1978), according to the following bi-exponential equation: C p = Ae -at Be + -at C where , p the is at serum in the drug of concentration time t; A is the intercept of the distribution phase with the concentration axis expressed as ug ml -1 ; B is the intercept of the elimination phase with the concentration axis expressed as ug ml -1 ; α is the distribution rate constant expressed in units of reciprocal time (h -1 ); β is the elimination rate constant expressed in units of reciprocal time (h -1 ); and e is the natural logarithm base.
Results were expressed asmean and standard error (S.E). Standard errors were calculated from the mean data according to Snedecor and Cochran (1976).
(1): Figure Semi-logarithmic graph depicting the time-concentration of tulathromycin in serum of goats after a single intravenous injection of 2.5 mg kg -1 b.wt alone (■) and with flunixin (A).

Results:
Disposition of tulathromycin in serum after intravenous injection was best fitted by the 2compartment open pharmacokinetic model (Figure 1). The pharmacokinetic parameters of tulathromycin following a single intravenous administration of 2.5 mg kg -1 b.wt alone and with flunixin are recorded in table (1). The results of the present study revealed that tulathromycin was rapidly distributed following intravenous injection when administrated with flunixin where the distrubtionhalf lives were when (t 0 . 5 ( α )) 0.071 given alone and 0.046 h with flunixin. The body clearance (Cl B ) was 0.46 and 0.17 l/kg.h, the volume of distribution at steadystate (Vd ss ) was 0.249 and 0.96 L/kg, respectively.  Basis Therapeutics.11th Ed. Med. Pub. Div., N.Y., Chic., San Franc., Lisbon, Lond., pp: 1173. Craig, A.W. andSuh, B. (1991)