PLASMA CONCENTRATioNS OF OXYTETRACYCLINE IN ELEPHANTS FOLLOWING INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION OF TERRAMYCIN/LA INJECTABLE SOLUTION

Limpoka M., P. Chai-anan, s. Sir i v e j pan d u, R. K a n c han 0 m a i, S. Rat tan a m 0 nth ian c h a i, P. P u a n g k u m: PlaAma Conce~On6 06 Oxyt~­ cycU.n.e .tn' Uephant.6 Following IntIulvenoUh and IntltamUhCulall Admi.YLL6:tJLalion 06 TeJrJr.amyc..i.n/La Injectable Solution. Acta vet. Brno,56,1987: 173-179. The blood concentrations 0' oxytetracycline were studied in Asian elephants following the intravenous and intramuscular administration of Terramycin/LA solution. The drug was administered as 200 mg oxytetracycline base/ml in aqueous 2 pyrrolidone at a dosage of 20 mg/kg body mass. The blood samples were collected from the ear veins of each animal. Plasma concentrations of oxytetracycline were analysed by microbiological method and high pressure liquid chromatography. An average peak plasma concentration of 6.2 ~g/ml was obtain,ed in one hour following intravenous administration in elephants. No oxytetracycline was detected in plasma after the 60th post dosing hour. The average peak plasma concentration of 2.87 ~g/ml was found in two hours followrng intramuscular injection of the drug. Concentrations exceeding 1 ~g/ml were maintained for 48 hours after intramuscular dose. The drug was shown to result in sustained oxytetracycline blood concentrations over a three-day period following a single intramuscular administration of the drug to elephants. Admi.YLL6:tJLalion 4Oute, p04t-inje~on time,OTC, eiephant.6. Asian elephants are susceptible to a number of diseasm for which antimicrobial drugs are recommended. The correct drugs'prescribed, proper dosage and proper interval in elephants are still questions. Too often, failure to treat an illness in elephants is caused by the inability of the

The blood concentrations 0' oxytetracycline were studied in Asian elephants following the intravenous and intramuscular administration of Terramycin/LA solution.The drug was administered as 200 mg oxytetracycline base/ml in aqueous 2 -pyrrolidone at a dosage of 20 mg/kg body mass.
The blood samples were collected from the ear veins of each animal.Plasma concentrations of oxytetracycline were analysed by microbiological method and high pressure liquid chromatography.
An average peak plasma concentration of 6.2 ~g/ml was obtain,ed in one hour following intravenous administration in elephants.No oxytetracycline was detected in plasma after the 60th post dosing hour.The average peak plasma concentration of 2.87 ~g/ml was found in two hours followrng intramuscular injection of the drug.Concentrations exceeding 1 ~g/ml were maintained for 48 hours after intramuscular dose.The drug was shown to result in sustained oxytetracycline blood concentrations over a three--day period following a single intramuscular administration of the drug to elephants.
Asian elephants are susceptible to a number of diseasm for which antimicrobial drugs are recommended.The correct drugs'prescribed, proper dosage and proper interval in elephants are still questions.Too often, failure to treat an illness in elephants is caused by the inability of the veterinarian to administer adequate doses and appropriate intervals of the drugs.S c h mid t (1978) proposed that elephants weighing the same as cattle and horses can be given the same dosage per unit of body mass, and 0.5 or 0.75 the recommended dose can be given to adult elephants.
In this study, blood concentrations of oxytetracycline were investigatt'-{ in Asian elephants following intravenous and intramuscular administration of 200 mg oxytetracycline base/ml in aqueous 2 -pyrrolidone at a dosage of 20 mg/kg body mass.Results obtained could be used as a guideline for recommended dosage regimen for clinical use of this antibiotic in elephants.

Animals
Six healthy Asian elephants l w~ighing 2.030 -3.475 kg were used in this study.The animals were acclimatized for 2 weeks around the experimental area 2 • The cannula 3 was placed in the right ear vein of each ,mimal prior to drug administration.The animals were randomly assigned to two groups.

Drug administration and blood collection
The drug used in this study was Terramyc~n/LA injectable solution 4 at the concentration of 200 mg of oxytetracycline base (OTC) /ml.The first three elephants received 10 ml of the drug/lOO kg body mass intravenously via the cannula.The three remaining elephants received the same dosage of Terramycin/LA solution intramuscularly.The deep muscular injection was distributed bilaterally in the hind quarters.No more than 30 ml of Terramycin/LA solution was injected into individual site.Disposable 3 in, 16 ga needles were used to inject the drug.No tranquilizer was given prior to drug administration or the collection of blood samples.The elephants were chained by one front leg to a fixed point only to obtain the blood samples.
Following drug administration, blood samples were collected in heparinized syringes at 0, 1, 2, 3, 4, 6, B, 12, IB, 24, 36, 4B, 60, B4, lOB, 132 hours post dosing.The blood samples were collected from the veins located on the posterior surface of the ears.After collection, the blood was centrifuged and the plasma was immediately frozen until assay.
Analytical method Plasma samples were analysed for OTC by a microbiological method.The microbiological assays were carried out in 150 x 20 mm petri dishes, with reference organism Ba.c.illu.6 c.Vte.U6 ATCC No. 1178 5 (B e nne t t et aI.1966).The limit of sensitivity of the method is 0.25 IJ g/mI.
Selected plasma samples were also analysed by high pressure liquid chromatography 6 (HPLC) (S h arm a and B e v i I I 197B   used in data analysis.Good correlation was found between the 2 assay methods.
The data was calculated on a SHARP PC -1500 with plotter/ Cassette Interface and CE -502 A Statistics Library.

Results and Discussion
The average plasma concentrations for intravenous injection of Terramycin/LA at 20 mg/kg body mass to elephants are shown in Table 1.One hour following drug administration an average plasma concentration of oxytetracycline was 6.19 \J g / ml.The drug in plasma decreased with time and reached 0.28 ]J g/ml (approximate limit of detection) about 18 hours after dosing.Concentrations exceeding 1 \J g/ml were maintained for at least 8 hours following intravenous adminrstration.A semilogarithmic plot of the average plasma concentrations at specific times following intravenous drug administration i~ illustrated in Figure 1. .The high pressure liquid chromatographic procedure was used to confirm the quantitation of oxytetracycline in plasma and to detect the presence of any metabolites.The concentrations of oxytetracycline in plasma of eleph-,nt no. 3, determined by both HPLC and the microbiological assay, are shown in Table 2.No metabolites were found in plasma of elephants receiving Terramycin/LA solution.
The individual and average concentrations of oxytetracycline in plasma following intramuscular administration of 20 mg Terramycin/LA/kg body mass to elephants are presented in Table 2.The average peak concentration of oxytetracycline in plasma was 2.87 ]J g / mI.This maximum value occurred two hours following drug administration.As shown in Table 3, the oxytetracycline concentration in plasma varied from 2.4 -3.6 \Jg/ml among individual animals at two hours.The concentrations exceeding 1 Il g/ml were maintained at least for 48 hours following intramuscular dosing.A semilogarithmic plot of an average plasma concentration vs time is presented in Figure 2.
After intramuscular injection of 20 mg/kg of the Terramycin/LA solution to elephants, peak plasma levels were achieved between 1 and 48 hours and ranged from 1. 09 -2.87 Il g/ml (Table 3).Plasma concentrations were higher than the minimal inhibitory concentrations (MIC) reported for most susceptible pathogens (0.5 Ilg/ml aTC) for approximately 84 hours, except for E. coli.The MIC values for E. c.oli have been reported to be 4 Il g I ml for aTC in a calf (G a r rod et al. 1973; A t kin son 198,3; Bar r y and Tho r n b e r r y 1980; R 0 sen b 1 a t t 1980), and this organism would probably be little affected on the i.m. dose employed.
It appears that the drug was rapidly absorbed and was shown to result in sustained aTC blood concentrations over •a three-day period in elephants following a single intramuscular injection of 20 mg/kg body mass.It is possible to compare the results in elephants with those reported elsewhere in cattle, sheep and swine (Technical Information, Agricultural Development Division, Pfizer Ltd. 1978-1981).

Fig. 2 :
Fig. 2: The average plasma concentrations of oxytetracycline following the i.m. administration of 20 mg Terramycin/LA solution/kg body mass to 3 elephants.
Concentrations of oxytetracycline in elephant plasma following the intravenous administration of 20 mg Terracyclin!LA solution!kilogram of body mass.